Publications by authors named "Dennis J Selkoe"

218 Publications

Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors.

Neuron 2021 Aug 26. Epub 2021 Aug 26.

Department of Biochemistry, Emory School of Medicine, Atlanta, GA, USA; Department of Neurology, Emory School of Medicine, Atlanta, GA, USA.

We have generated a controlled and manipulable resource that captures genetic risk for Alzheimer's disease: iPSC lines from 53 individuals coupled with RNA and proteomic profiling of both iPSC-derived neurons and brain tissue of the same individuals. Data collected for each person include genome sequencing, longitudinal cognitive scores, and quantitative neuropathology. The utility of this resource is exemplified here by analyses of neurons derived from these lines, revealing significant associations between specific Aβ and tau species and the levels of plaque and tangle deposition in the brain and, more importantly, with the trajectory of cognitive decline. Proteins and networks are identified that are associated with AD phenotypes in iPSC neurons, and relevant associations are validated in brain. The data presented establish this iPSC collection as a resource for investigating person-specific processes in the brain that can aid in identifying and validating molecular pathways underlying AD.
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http://dx.doi.org/10.1016/j.neuron.2021.08.003DOI Listing
August 2021

Treatments for Alzheimer's disease emerge.

Authors:
Dennis J Selkoe

Science 2021 Aug;373(6555):624-626

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1126/science.abi6401DOI Listing
August 2021

Wild-type GBA1 increases the α-synuclein tetramer-monomer ratio, reduces lipid-rich aggregates, and attenuates motor and cognitive deficits in mice.

Proc Natl Acad Sci U S A 2021 Aug;118(31)

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115

Loss-of-function mutations in acid beta-glucosidase 1 (GBA1) are among the strongest genetic risk factors for Lewy body disorders such as Parkinson's disease (PD) and Lewy body dementia (DLB). Altered lipid metabolism in PD patient-derived neurons, carrying either GBA1 or PD αS mutations, can shift the physiological α-synuclein (αS) tetramer-monomer (T:M) equilibrium toward aggregation-prone monomers. A resultant increase in pSer129+ αS monomers provides a likely building block for αS aggregates. 3K αS mice, representing a neuropathological amplification of the E46K PD-causing mutation, have decreased αS T:M ratios and vesicle-rich αS+ aggregates in neurons, accompanied by a striking PD-like motor syndrome. We asked whether enhancing glucocerebrosidase (GCase) expression could benefit αS dyshomeostasis by delivering an adeno-associated virus (AAV)-human wild-type (wt) GBA1 vector into the brains of 3K neonates. Intracerebroventricular AAV-wtGBA1 at postnatal day 1 resulted in prominent forebrain neuronal GCase expression, sustained through 6 mo. GBA1 attenuated behavioral deficits both in working memory and fine motor performance tasks. Furthermore, wtGBA1 increased αS solubility and the T:M ratio in both 3K-GBA mice and control littermates and reduced pS129+ and lipid-rich aggregates in 3K-GBA. We observed GCase distribution in more finely dispersed lysosomes, in which there was increased GCase activity, lysosomal cathepsin D and B maturation, decreased perilipin-stabilized lipid droplets, and a normalized TFEB translocation to the nucleus, all indicative of improved lysosomal function and lipid turnover. Therefore, a prolonged increase of the αS T:M ratio by elevating GCase activity reduced the lipid- and vesicle-rich aggregates and ameliorated PD-like phenotypes in mice, further supporting lipid modulating therapies in PD.
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http://dx.doi.org/10.1073/pnas.2103425118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346893PMC
August 2021

Altered conformation of α-synuclein drives dysfunction of synaptic vesicles in a synaptosomal model of Parkinson's disease.

Cell Rep 2021 Jul;36(1):109333

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address:

While misfolding of alpha-synuclein (αSyn) is central to the pathogenesis of Parkinson's disease (PD), fundamental questions about its structure and function at the synapse remain unanswered. We examine synaptosomes from non-transgenic and transgenic mice expressing wild-type human αSyn, the E46K fPD-causing mutation, or an amplified form of E46K ("3K"). Synaptosomes from mice expressing the 3K mutant show reduced Ca-dependent vesicle exocytosis, altered synaptic vesicle ultrastructure, decreased SNARE complexes, and abnormal levels of certain synaptic proteins. With our intra-synaptosomal nuclear magnetic resonance (NMR) method, we reveal that WT αSyn participates in heterogeneous interactions with synaptic components dependent on endogenous αSyn and synaptosomal integrity. The 3K mutation markedly alters these interactions. The synaptic microenvironment is necessary for αSyn to reach its native conformations and establish a physiological interaction network. Its inability to populate diverse conformational ensembles likely represents an early step in αSyn dysfunction that contributes to the synaptotoxicity observed in synucleinopathies.
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http://dx.doi.org/10.1016/j.celrep.2021.109333DOI Listing
July 2021

Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides.

J Biol Chem 2021 Jan-Jun;296:100393. Epub 2021 Feb 8.

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

γ-Secretase is responsible for the proteolysis of amyloid precursor protein (APP) into amyloid-beta (Aβ) peptides, which are centrally implicated in the pathogenesis of Alzheimer's disease (AD). The biochemical mechanism of how processing by γ-secretase is regulated, especially as regards the interaction between enzyme and substrate, remains largely unknown. Here, mutagenesis reveals that the hydrophilic loop-1 (HL-1) of presenilin-1 (PS1) is critical for both γ-secretase step-wise cleavages (processivity) and its allosteric modulation by heterocyclic γ-modulatory compounds. Systematic mutagenesis of HL-1, including all of its familial AD mutations and additional engineered variants, and quantification of the resultant Aβ products show that HL-1 is necessary for proper sequential γ-secretase processivity. We identify Y106, L113, and Y115 in HL-1 as key targets for heterocyclic γ-secretase modulators (GSMs) to stimulate processing of pathogenic Aβ peptides. Further, we confirm that the GxxxG domain in the APP transmembrane region functions as a critical substrate motif for γ-secretase processivity: a G29A substitution in APP-C99 mimics the beneficial effects of GSMs. Together, these findings provide a molecular basis for the structural regulation of γ-processivity by enzyme and substrate, facilitating the rational design of new GSMs that lower AD-initiating amyloidogenic Aβ peptides.
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http://dx.doi.org/10.1016/j.jbc.2021.100393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961089PMC
September 2021

Plasma N-terminal tau fragment levels predict future cognitive decline and neurodegeneration in healthy elderly individuals.

Nat Commun 2020 11 27;11(1):6024. Epub 2020 Nov 27.

Brigham and Women's Hospital, Boston, MA, USA.

The availability of blood-based assays detecting Alzheimer's disease (AD) pathology should greatly accelerate AD therapeutic development and improve clinical care. This is especially true for markers that capture the risk of decline in pre-symptomatic stages of AD, as this would allow one to focus interventions on participants maximally at risk and at a stage prior to widespread synapse loss and neurodegeneration. Here we quantify plasma concentrations of an N-terminal fragment of tau (NT1) in a large, well-characterized cohort of clinically normal elderly who were followed longitudinally. Plasma NT1 levels at study entry (when all participants were unimpaired) were highly predictive of future cognitive decline, pathological tau accumulation, neurodegeneration, and transition to a diagnosis of MCI/AD. These predictive effects were particularly strong in participants with even modestly elevated brain β-amyloid burden at study entry, suggesting plasma NT1 levels capture very early cognitive, pathologic and neurodegenerative changes along the AD trajectory.
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http://dx.doi.org/10.1038/s41467-020-19543-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695712PMC
November 2020

Upregulation of Cellular Palmitoylation Mitigates α-Synuclein Accumulation and Neurotoxicity.

Mov Disord 2021 02 26;36(2):348-359. Epub 2020 Oct 26.

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Background: Synucleinopathies, including Parkinson's disease (PD), are characterized by α-synuclein (αS) cytoplasmic inclusions. αS-dependent vesicle-trafficking defects are important in PD pathogenesis, but their mechanisms are not well understood. Protein palmitoylation, post-translational addition of the fatty acid palmitate to cysteines, promotes trafficking by anchoring specific proteins to the vesicle membrane. αS itself cannot be palmitoylated as it lacks cysteines, but it binds to membranes, where palmitoylation occurs, via an amphipathic helix. We hypothesized that abnormal αS membrane-binding impairs trafficking by disrupting palmitoylation. Accordingly, we investigated the therapeutic potential of increasing cellular palmitoylation.

Objectives: We asked whether upregulating palmitoylation by inhibiting the depalmitoylase acyl-protein-thioesterase-1 (APT1) ameliorates pathologic αS-mediated cellular phenotypes and sought to identify the mechanism.

Methods: Using human neuroblastoma cells, rat neurons, and iPSC-derived PD patient neurons, we examined the effects of pharmacologic and genetic downregulation of APT1 on αS-associated phenotypes.

Results: APT1 inhibition or knockdown decreased αS cytoplasmic inclusions, reduced αS serine-129 phosphorylation (a PD neuropathological marker), and protected against αS-dependent neurotoxicity. We identified the APT1 substrate microtubule-associated-protein-6 (MAP6), which binds to vesicles in a palmitoylation-dependent manner, as a key mediator of these effects. Mechanistically, we found that pathologic αS accelerated palmitate turnover on MAP6, suggesting that APT1 inhibition corrects a pathological αS-dependent palmitoylation deficit. We confirmed the disease relevance of this mechanism by demonstrating decreased MAP6 palmitoylation in neurons from αS gene triplication patients.

Conclusions: Our findings demonstrate a novel link between the fundamental process of palmitoylation and αS pathophysiology. Upregulating palmitoylation represents an unexplored therapeutic strategy for synucleinopathies. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28346DOI Listing
February 2021

A Stearoyl-Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in α-Synuclein Mice.

Ann Neurol 2021 01 23;89(1):74-90. Epub 2020 Oct 23.

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Objective: Parkinson disease (PD) has useful symptomatic treatments that do not slow the neurodegenerative process, and no significant disease-modifying treatments are approved. A key therapeutic target in PD is α-synuclein (αS), which is both genetically implicated and accumulates in Lewy bodies rich in vesicles and other lipid membranes. Reestablishing αS homeostasis is a central goal in PD. Based on previous lipidomic analyses, we conducted a mouse trial of a stearoyl-coenzyme A desaturase (SCD) inhibitor ("5b") that prevented αS-positive vesicular inclusions and cytotoxicity in cultured human neurons.

Methods: Oral dosing and brain activity of 5b were established in nontransgenic mice. 5b in drinking water was given to mice expressing wild-type human αS (WT) or an amplified familial PD αS mutation (E35K + E46K + E61K ["3K"]) beginning near the onset of nigral and cortical neurodegeneration and the robust PD-like motor syndrome in 3K. Motor phenotypes, brain cytopathology, and SCD-related lipid changes were quantified in 5b- versus placebo-treated mice. Outcomes were compared to effects of crossing 3K to SCD1 mice.

Results: 5b treatment reduced αS hyperphosphorylation in E46K-expressing human neurons, in 3K neural cultures, and in both WT and 3K αS mice. 5b prevented subtle gait deficits in WT αS mice and the PD-like resting tremor and progressive motor decline of 3K αS mice. 5b also increased αS tetramers and reduced proteinase K-resistant lipid-rich aggregates. Similar benefits accrued from genetically deleting 1 SCD allele, providing target validation.

Interpretation: Prolonged reduction of brain SCD activity prevented PD-like neuropathology in multiple PD models. Thus, an orally available SCD inhibitor potently ameliorates PD phenotypes, positioning this approach to treat human α-synucleinopathies. ANN NEUROL 2021;89:74-90.
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http://dx.doi.org/10.1002/ana.25920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756464PMC
January 2021

Potential human transmission of amyloid β pathology: surveillance and risks.

Lancet Neurol 2020 10 16;19(10):872-878. Epub 2020 Sep 16.

Department of Neurosurgery, University Hospitals Leuven, Leuven, Belgium.

Studies in experimental animals show transmissibility of amyloidogenic proteins associated with prion diseases, Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Although these data raise potential concerns for public health, convincing evidence for human iatrogenic transmission only exists for prions and amyloid β after systemic injections of contaminated growth hormone extracts or dura mater grafts derived from cadavers. Even though these procedures are now obsolete, some reports raise the possibility of iatrogenic transmission of amyloid β through putatively contaminated neurosurgical equipment. Iatrogenic transmission of amyloid β might lead to amyloid deposition in the brain parenchyma and blood vessel walls, potentially resulting in cerebral amyloid angiopathy after several decades. Cerebral amyloid angiopathy can cause life-threatening brain haemorrhages; yet, there is no proof that the transmission of amyloid β can also lead to Alzheimer's dementia. Large, long-term epidemiological studies and sensitive, cost-efficient tools to detect amyloid are needed to better understand any potential routes of amyloid β transmission and to clarify whether other similar proteopathic seeds, such as tau or α-synuclein, can also be transferred iatrogenically.
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http://dx.doi.org/10.1016/S1474-4422(20)30238-6DOI Listing
October 2020

Analysis of α-synuclein species enriched from cerebral cortex of humans with sporadic dementia with Lewy bodies.

Brain Commun 2020 11;2(1):fcaa010. Epub 2020 Feb 11.

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Since researchers identified α-synuclein as the principal component of Lewy bodies and Lewy neurites, studies have suggested that it plays a causative role in the pathogenesis of dementia with Lewy bodies and other 'synucleinopathies'. While α-synuclein dyshomeostasis likely contributes to the neurodegeneration associated with the synucleinopathies, few direct biochemical analyses of α-synuclein from diseased human brain tissue currently exist. In this study, we analysed sequential protein extracts from a substantial number of patients with neuropathological diagnoses of dementia with Lewy bodies and corresponding controls, detecting a shift of cytosolic and membrane-bound physiological α-synuclein to highly aggregated forms. We then fractionated aqueous extracts (cytosol) from cerebral cortex using non-denaturing methods to search for soluble, disease-associated high molecular weight species potentially associated with toxicity. We applied these fractions and corresponding insoluble fractions containing Lewy-type aggregates to several reporter assays to determine their bioactivity and cytotoxicity. Ultimately, high molecular weight cytosolic fractions enhances phospholipid membrane permeability, while insoluble, Lewy-associated fractions induced morphological changes in the neurites of human stem cell-derived neurons. While the concentrations of soluble, high molecular weight α-synuclein were only slightly elevated in brains of dementia with Lewy bodies patients compared to healthy, age-matched controls, these observations suggest that a small subset of soluble α-synuclein aggregates in the brain may drive early pathogenic effects, while Lewy body-associated α-synuclein can drive neurotoxicity.
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http://dx.doi.org/10.1093/braincomms/fcaa010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7130446PMC
February 2020

Amyloid β-protein and beyond: the path forward in Alzheimer's disease.

Curr Opin Neurobiol 2020 04;61:116-124

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States. Electronic address:

Basic research on the biological mechanism of Alzheimer's disease has focused for decades on the age-related aggregation of the amyloid β-protein and its apparent downstream effects on microglia, astrocytes and neurons, including the posttranslational modification of the tau protein that seems necessary for symptom expression. Here, we discuss the highly challenging process of developing disease-modifying therapies and highlight several key areas of current research that are progressing in exciting directions. We conclude that further deep molecular analyses of the disease, including the mechanisms of β-amyloidosis, will enable more effective clinical trials and ultimately achieve the progress that our patients so deserve.
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http://dx.doi.org/10.1016/j.conb.2020.02.003DOI Listing
April 2020

Dynamics of plasma biomarkers in Down syndrome: the relative levels of Aβ42 decrease with age, whereas NT1 tau and NfL increase.

Alzheimers Res Ther 2020 03 19;12(1):27. Epub 2020 Mar 19.

Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Road, Boston, MA, 02115, USA.

Background: Down syndrome (DS) is the most common genetic cause of Alzheimer's disease (AD), but diagnosis of AD in DS is challenging due to the intellectual disability which accompanies DS. When disease-modifying agents for AD are approved, reliable biomarkers will be required to identify when and how long people with DS should undergo treatment. Three cardinal neuropathological features characterize AD, and AD in DS-Aβ amyloid plaques, tau neurofibrillary tangles, and neuronal loss. Here, we quantified plasma biomarkers of all 3 neuropathological features in a large cohort of people with DS aged from 3 months to 68 years. Our primary aims were (1) to assess changes in the selected plasma biomarkers in DS across age, and (2) to compare biomarkers measured in DS plasma versus age- and sex-matched controls.

Methods: Using ultra-sensitive single molecule array (Simoa) assays, we measured 3 analytes (Aβ42, NfL, and tau) in plasmas of 100 individuals with DS and 100 age- and sex-matched controls. Tau was measured using an assay (NT1) which detects forms of tau containing at least residues 6-198. The stability of the 3 analytes was established using plasma from ten healthy volunteers collected at 6 intervals over a 5-day period.

Results: High Aβ42 and NT1 tau and low NfL were observed in infants. Across all ages, Aβ42 levels were higher in DS than controls. Levels of Aβ42 decreased with age in both DS and controls, but this decrease was greater in DS than controls and became prominent in the third decade of life. NT1 tau fell in adolescents and young adults, but increased in older individuals with DS. NfL levels were low in infants, children, adolescents, and young adults, but thereafter increased in DS compared to controls.

Conclusions: High levels of Aβ42 and tau in both young controls and DS suggest these proteins are produced by normal physiological processes, whereas the changes seen in later life are consistent with emergence of pathological alterations. These plasma biomarker results are in good agreement with prior neuropathology studies and indicate that the third and fourth decades (i.e., 20 to 40 years of age) of life are pivotal periods during which AD processes manifest in DS. Application of the assays used here to longitudinal studies of individuals with DS aged 20 to 50 years of age should further validate the use of these biomarkers, and in time may allow identification and monitoring of people with DS best suited for treatment with AD therapies.
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http://dx.doi.org/10.1186/s13195-020-00593-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081580PMC
March 2020

A mechanistic hypothesis for the impairment of synaptic plasticity by soluble Aβ oligomers from Alzheimer's brain.

J Neurochem 2020 09 5;154(6):583-597. Epub 2020 Apr 5.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

It is increasingly accepted that early cognitive impairment in Alzheimer's disease results in considerable part from synaptic dysfunction caused by the accumulation of a range of oligomeric assemblies of amyloid β-protein (Aβ). Most studies have used synthetic Aβ peptides to explore the mechanisms of memory deficits in rodent models, but recent work suggests that Aβ assemblies isolated from human (AD) brain tissue are far more potent and disease-relevant. Although reductionist experiments show Aβ oligomers to impair synaptic plasticity and neuronal viability, the responsible mechanisms are only partly understood. Glutamatergic receptors, GABAergic receptors, nicotinic receptors, insulin receptors, the cellular prion protein, inflammatory mediators, and diverse signaling pathways have all been suggested. Studies using AD brain-derived soluble Aβ oligomers suggest that only certain bioactive forms (principally small, diffusible oligomers) can disrupt synaptic plasticity, including by binding to plasma membranes and changing excitatory-inhibitory balance, perturbing mGluR, PrP, and other neuronal surface proteins, down-regulating glutamate transporters, causing glutamate spillover, and activating extrasynaptic GluN2B-containing NMDA receptors. We synthesize these emerging data into a mechanistic hypothesis for synaptic failure in Alzheimer's disease that can be modified as new knowledge is added and specific therapeutics are developed.
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http://dx.doi.org/10.1111/jnc.15007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487043PMC
September 2020

miR-212 and miR-132 Are Downregulated in Neurally Derived Plasma Exosomes of Alzheimer's Patients.

Front Neurosci 2019 26;13:1208. Epub 2019 Nov 26.

Laboratory for Neurodegenerative Disease Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

It was recently discovered that brain cells release extracellular vesicles (EV) which can pass from brain into blood. These findings raise the possibility that brain-derived EV's present in blood can be used to monitor disease processes occurring in the cerebrum. Since the levels of certain micro-RNAs (miRNAs) have been reported to be altered in Alzheimer's disease (AD) brain, we sought to assess miRNA dysregulation in AD brain tissue and to determine if these changes were reflected in neural EVs isolated from blood of subjects with AD. To this end, we employed high-content miRNA arrays to search for differences in miRNAs in RNA pools from brain tissue of AD ( = 5), high pathological control (HPC) ( = 5), or cognitively intact pathology-free controls ( = 5). Twelve miRNAs were altered by >1.5-fold in AD compared to controls, and six of these were also changed compared to HPCs. Analysis of hits in brain extracts from 11 AD, 7 HPCs and 9 controls revealed a similar fold difference in these six miRNAs, with three showing statistically significant group differences and one with a strong trend toward group differences. Thereafter, we focused on the four miRNAs that showed group differences and measured their content in neurally derived blood EVs isolated from 63 subjects: 16 patients with early stage dementia and a CSF Aβ42+ tau profile consistent with AD, 16 individuals with mild cognitive impairment (MCI) and an AD CSF profile, and 31 cognitively intact controls with normal CSF Aβ42+ tau levels. ROC analysis indicated that measurement of miR-132-3p in neurally-derived plasma EVs showed good sensitivity and specificity to diagnose AD, but did not effectively separate individuals with AD-MCI from controls. Moreover, when we measured the levels of a related miRNA, miR-212, we found that this miRNA was also decreased in neural EVs from AD patients compared to controls. Our results suggest that measurement of miR-132 and miR-212 in neural EVs should be further investigated as a diagnostic aid for AD and as a potential theragnostic.
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http://dx.doi.org/10.3389/fnins.2019.01208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902042PMC
November 2019

Environmental enrichment prevents Aβ oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathways.

Neurobiol Dis 2020 02 24;134:104617. Epub 2019 Oct 24.

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of America. Electronic address:

As the most common cause of progressive cognitive decline in humans, Alzheimer's disease (AD) has been intensively studied, but the mechanisms underlying its profound synaptic dysfunction remain unclear. Here we confirm that exposing wild-type mice to an enriched environment (EE) facilitates signaling in the hippocampus that promotes long-term potentiation (LTP). Exposing the hippocampus of mice kept in standard housing to soluble Aβ oligomers impairs LTP, but EE can fully prevent this. Mechanistically, the key molecular features of the EE benefit are an upregulation of miRNA-132 and an inhibition of histone deacetylase (HDAC) signaling. Specifically, soluble Aβ oligomers decreased miR-132 expression and increased HDAC3 levels in cultured primary neurons. Further, we provide evidence that HDAC3 is a direct target of miR-132. Overexpressing miR-132 or injecting an HDAC3 inhibitor into mice in standard housing mimics the benefits of EE in enhancing hippocampal LTP and preventing hippocampal impairment by Aβ oligomers in vivo. We conclude that EE enhances hippocampal synaptic plasticity by upregulating miRNA-132 and reducing HDAC3 signaling in a way that counteracts the synaptotoxicity of human Aβ oligomers. Our findings provide a rationale for prolonged exposure to cognitive novelty and/or epigenetic modulation to lessen the progressive effects of Aβ accumulation during human brain aging.
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http://dx.doi.org/10.1016/j.nbd.2019.104617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243177PMC
February 2020

A novel V272D presenilin mutation associated with logopenia, disorientation, and apraxia in an autosomal-dominant Alzheimer's disease family.

Neurobiol Aging 2020 01 7;85:154.e5-154.e7. Epub 2019 Aug 7.

Chair of Geriatric Medicine, University Essen, and Geriatric Centre Haus Berge, Contilia Group, Essen, Germany; Department of Neurology, Philipps-University Marburg, Marburg, Germany. Electronic address:

In the present study, a novel mutation in the presenilin 1 gene was discovered in an Iraq-native patient with early-onset Alzheimer's disease, who presented with speech impairment and memory decline at age 46 years. Magnetic resonance imaging showed a frontotemporal atrophy. Sanger sequencing identified a heterozygous T to A transversion at position 815 (c.815T>A) in the presenilin 1 gene (PSEN1), resulting in a novel missense mutation at codon 272 from valine to aspartate (V272D). We tested this PSEN1 mutation in vitro and found V272D resulted in an altered Aβ42/40 ratio.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.07.002DOI Listing
January 2020

Multiple BACE1 inhibitors abnormally increase the BACE1 protein level in neurons by prolonging its half-life.

Alzheimers Dement 2019 09 12;15(9):1183-1194. Epub 2019 Aug 12.

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Introduction: There is keen interest in elucidating the biological mechanisms underlying recent failures of β-site amyloid precursor protein-cleaving enzyme-1 (BACE1) inhibitors in Alzheimer's disease trials.

Methods: We developed a highly sensitive and specific immunoassay for BACE1 in cell lines and iPSC-derived human neurons to systematically analyze the effects of eight clinically relevant BACE1 inhibitors.

Results: Seven of 8 inhibitors elevated BACE1 protein levels. Among protease inhibitors tested, the elevation was specific to BACE1 inhibitors. The inhibitors did not increase BACE1 transcription but extended the protein's half-life. BACE1 became elevated at concentrations below the IC for amyloid β (Aβ).

Discussion: Elevation of BACE1 by 7 of 8 BACE1 inhibitors raises new concerns about advancing such β-secretase inhibitors for AD. Chronic elevation could lead to intermittently uninhibited BACE1 when orally dosed inhibitors reach trough levels, abnormally increasing substrate processing. Compounds such as roburic acid that lower Aβ by dissociating β/γ secretase complexes are better candidates because they neither inhibit β- and γ-secretase nor increase BACE1 levels.
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http://dx.doi.org/10.1016/j.jalz.2019.06.3918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756967PMC
September 2019

Early network dysfunction in Alzheimer's disease.

Authors:
Dennis J Selkoe

Science 2019 08;365(6453):540-541

Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1126/science.aay5188DOI Listing
August 2019

Target engagement in an alzheimer trial: Crenezumab lowers amyloid β oligomers in cerebrospinal fluid.

Ann Neurol 2019 08 22;86(2):215-224. Epub 2019 Jun 22.

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Objective: Oligomeric forms of amyloid β protein (oAβ) are believed to be principally responsible for neurotoxicity in Alzheimer disease (AD), but it is not known whether anti-Aβ antibodies are capable of lowering oAβ levels in humans.

Methods: We developed an ultrasensitive immunoassay and used it to measure oAβ in cerebrospinal fluid (CSF) from 104 AD subjects participating in the ABBY and BLAZE phase 2 trials of the anti-Aβ antibody crenezumab. Patients received subcutaneous (SC) crenezumab (300mg) or placebo every 2 weeks, or intravenous (IV) crenezumab (15mg/kg) or placebo every 4 weeks for 68 weeks. Ninety-eight of the 104 patients had measurable baseline oAβ levels, and these were compared to levels at week 69 in placebo (n = 28), SC (n = 35), and IV (n = 35) treated patients.

Results: Among those receiving crenezumab, 89% of SC and 86% of IV patients had lower levels of oAβ at week 69 versus baseline. The difference in the proportion of patients with decreasing levels was significant for both treatment arms: p = 0.0035 for SC and p = 0.01 for IV crenezumab versus placebo. The median percentage change was -48% in the SC arm and -43% in the IV arm. No systematic change was observed in the placebo group, with a median change of -13% and equivalent portions with negative and positive change.

Interpretation: Crenezumab lowered CSF oAβ levels in the large majority of treated patients tested. These results support engagement of the principal pathobiological target in AD and identify CSF oAβ as a novel pharmacodynamic biomarker for use in trials of anti-Aβ agents. ANN NEUROL 2019;86:215-224.
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http://dx.doi.org/10.1002/ana.25513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771589PMC
August 2019

Alzheimer disease and aducanumab: adjusting our approach.

Authors:
Dennis J Selkoe

Nat Rev Neurol 2019 07;15(7):365-366

Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41582-019-0205-1DOI Listing
July 2019

Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer's brain.

Brain 2019 05;142(5):1441-1457

Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

The primary structure of canonical amyloid-β-protein was elucidated more than 30 years ago, yet the forms of amyloid-β that play a role in Alzheimer's disease pathogenesis remain poorly defined. Studies of Alzheimer's disease brain extracts suggest that amyloid-β, which migrates on sodium dodecyl sulphate polyacrylamide gel electrophoresis with a molecular weight of ∼7 kDa (7kDa-Aβ), is particularly toxic; however, the nature of this species has been controversial. Using sophisticated mass spectrometry and sensitive assays of disease-relevant toxicity we show that brain-derived bioactive 7kDa-Aβ contains a heterogeneous mixture of covalently cross-linked dimers in the absence of any other detectable proteins. The identification of amyloid-β dimers may open a new phase of Alzheimer's research and allow a better understanding of Alzheimer's disease, and how to monitor and treat this devastating disorder. Future studies investigating the bioactivity of individual dimers cross-linked at known sites will be critical to this effort.
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http://dx.doi.org/10.1093/brain/awz066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487330PMC
May 2019

A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor.

J Cell Biol 2019 02 9;218(2):644-663. Epub 2019 Jan 9.

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

Intramembrane proteolysis of transmembrane substrates by the presenilin-γ-secretase complex is preceded and regulated by shedding of the substrate's ectodomain by α- or β-secretase. We asked whether β- and γ-secretases interact to mediate efficient sequential processing of APP, generating the amyloid β (Aβ) peptides that initiate Alzheimer's disease. We describe a hitherto unrecognized multiprotease complex containing active β- and γ-secretases. BACE1 coimmunoprecipitated and cofractionated with γ-secretase in cultured cells and in mouse and human brain. An endogenous high molecular weight (HMW) complex (∼5 MD) containing β- and γ-secretases and holo-APP was catalytically active in vitro and generated a full array of Aβ peptides, with physiological Aβ42/40 ratios. The isolated complex responded properly to γ-secretase modulators. Alzheimer's-causing mutations in presenilin altered the Aβ42/40 peptide ratio generated by the HMW β/γ-secretase complex indistinguishably from that observed in whole cells. Thus, Aβ is generated from holo-APP by a BACE1-γ-secretase complex that provides sequential, efficient RIP processing of full-length substrates to final products.
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http://dx.doi.org/10.1083/jcb.201806205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363461PMC
February 2019

Learnings about the complexity of extracellular tau aid development of a blood-based screen for Alzheimer's disease.

Alzheimers Dement 2019 03 9;15(3):487-496. Epub 2018 Nov 9.

Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England. Electronic address:

Introduction: The tau protein plays a central role in Alzheimer's disease (AD), and there is huge interest in measuring tau in blood and cerebrospinal fluid (CSF).

Methods: We developed a set of immunoassays to measure tau in specimens from humans diagnosed based on current best clinical and CSF biomarker criteria.

Results: In CSF, mid-region- and N-terminal-detected tau predominated and rose in disease. In plasma, an N-terminal assay (NT1) detected elevated levels of tau in AD and AD-mild cognitive impairment (MCI). Plasma NT1 measurements separated controls from AD-MCI (area under the curve [AUC] = 0.88) and AD (AUC = 0.96) in a discovery cohort and in a Validation Cohort (with AUCs = 0.79 and 0.75, respectively).

Discussion: The forms of tau in CSF and plasma are distinct, but in each specimen type, the levels of certain fragments are increased in AD. Measurement of plasma NT1 tau should be aggressively pursued as a potential blood-based screening test for AD/AD-MCI.
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http://dx.doi.org/10.1016/j.jalz.2018.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476313PMC
March 2019

Decoding the synaptic dysfunction of bioactive human AD brain soluble Aβ to inspire novel therapeutic avenues for Alzheimer's disease.

Acta Neuropathol Commun 2018 11 8;6(1):121. Epub 2018 Nov 8.

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Road, Boston, MA, 02115, USA.

Pathologic, biochemical and genetic evidence indicates that accumulation and aggregation of amyloid β-proteins (Aβ) is a critical factor in the pathogenesis of Alzheimer's disease (AD). Several therapeutic interventions attempting to lower Aβ have failed to ameliorate cognitive decline in patients with clinical AD significantly, but most such approaches target only one or two facets of Aβ production/clearance/toxicity and do not consider the heterogeneity of human Aβ species. As synaptic dysfunction may be among the earliest deficits in AD, we used hippocampal long-term potentiation (LTP) as a sensitive indicator of the early neurotoxic effects of Aβ species. Here we confirmed prior findings that soluble Aβ oligomers, much more than fibrillar amyloid plaque cores or Aβ monomers, disrupt synaptic function. Interestingly, not all (84%) human AD brain extracts are able to inhibit LTP and the degree of LTP impairment by AD brain extracts does not correlate with Aβ levels detected by standard ELISAs. Bioactive AD brain extracts also induce neurotoxicity in iPSC-derived human neurons. Shorter forms of Aβ (including Aβ, Aβ, Aβ), pre-Aβ APP fragments (- 30 to - 1) and N-terminally extended Aβs (- 30 to + 40) each showed much less synaptotoxicity than longer Aβs (Aβ - Aβ). We found that antibodies which target the N-terminus, not the C-terminus, efficiently rescued Aβ oligomer-impaired LTP and oligomer-facilitated LTD. Our data suggest that preventing soluble Aβ oligomer formation and targeting their N-terminal residues with antibodies could be an attractive combined therapeutic approach.
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http://dx.doi.org/10.1186/s40478-018-0626-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225562PMC
November 2018

Abrogating Native α-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome Closely Resembling Parkinson's Disease.

Neuron 2018 10;100(1):75-90.e5

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address:

α-Synuclein (αS) regulates vesicle exocytosis but forms insoluble deposits in Parkinson's disease (PD). Developing disease-modifying therapies requires animal models that reproduce cardinal features of PD. We recently described a previously unrecognized physiological form of αS, α-helical tetramers, and showed that familial PD-causing missense mutations shift tetramers to aggregation-prone monomers. Here, we generated mice expressing the fPD E46K mutation plus 2 homologous E→K mutations in adjacent KTKEGV motifs. This tetramer-abrogating mutant causes phenotypes similar to PD. αS monomers accumulate at membranes and form vesicle-rich inclusions. αS becomes insoluble, proteinase K-resistant, Ser129-phosphorylated, and C-terminally truncated, as in PD. These changes affect regions controlling motor behavior, including a decrease in nigrostriatal dopaminergic neurons. The outcome is a progressive motor syndrome including tremor and gait and limb deficits partially responsive to L-DOPA. This fully penetrant phenotype indicates that tetramers are required for normal αS homeostasis and that chronically shifting tetramers to monomers may result in PD, with attendant therapeutic implications.
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http://dx.doi.org/10.1016/j.neuron.2018.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211795PMC
October 2018

Light at the End of the Amyloid Tunnel.

Authors:
Dennis J Selkoe

Biochemistry 2018 10 1;57(41):5921-5922. Epub 2018 Oct 1.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital , Harvard Medical School , Boston , Massachusetts 02115 , United States.

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http://dx.doi.org/10.1021/acs.biochem.8b00985DOI Listing
October 2018

Soluble Aβ Oligomers Impair Dipolar Heterodendritic Plasticity by Activation of mGluR in the Hippocampal CA1 Region.

iScience 2018 Aug 24;6:138-150. Epub 2018 Jul 24.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Soluble Aβ oligomers (oAβs) contribute importantly to synaptotoxicity in Alzheimer disease (AD), but the mechanisms related to heterogeneity of synaptic functions at local circuits remain elusive. Nearly all studies of the effects of oAβs on hippocampal synaptic plasticity have only examined homosynaptic plasticity. Here we stimulated the Schaffer collaterals and then simultaneously recorded in stratum radiatum (apical dendrites) and stratum oriens (basal dendrites) of CA1 neurons. We found that the apical dendrites are significantly more vulnerable to oAβ-mediated synaptic dysfunction: the heterosynaptic basal dendritic long-term potentiation (LTP) remained unchanged, whereas the homosynaptic apical LTP was impaired. However, the heterosynaptic basal dendritic plasticity induced by either spaced 10-Hz bursts or low-frequency (1-Hz) stimulation was disrupted by oAβs in a mGluR5-dependent manner. These results suggest that different firing patterns in the same neurons may be selectively altered by soluble oAβs in an early phase of AD, before frank neurodegeneration.
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http://dx.doi.org/10.1016/j.isci.2018.07.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137707PMC
August 2018

Enriched environment enhances β-adrenergic signaling to prevent microglia inflammation by amyloid-β.

EMBO Mol Med 2018 09;10(9)

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA

Environmental enrichment (EE) is a rodent behavioral paradigm that can model the cognitive benefits to humans associated with intellectual activity and exercise. We recently discovered EE's anti-inflammatory protection of brain microglia against soluble oligomers of human amyloid β-protein (oAβ). Mechanistically, we report that the key factor in microglial protection by EE is chronically enhanced β-adrenergic signaling. Quantifying microglial morphology and inflammatory RNA profiles revealed that mice in standard housing (SH) fed the β-adrenergic agonist isoproterenol experienced similar protection of microglia against oAβ-induced inflammation as did mice in EE Conversely, mice in EE fed the β-adrenergic antagonist propranolol lost microglial protection against oAβ. Mice lacking β1/β2-adrenergic receptors showed no protection of microglia by EE In SH mice, quantification of norepinephrine in hippocampus and interstitial fluid showed that oAβ disrupted norepinephrine homeostasis, and microglial-specific analysis of β2-adrenergic receptors indicated a decreased receptor level. Both features were rescued by EE Thus, enhanced β-adrenergic signaling at the ligand and receptor levels mediates potent benefits of EE on microglial inflammation induced by human Aβ oligomers .
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http://dx.doi.org/10.15252/emmm.201808931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127891PMC
September 2018

An in vitro paradigm to assess potential anti-Aβ antibodies for Alzheimer's disease.

Nat Commun 2018 07 11;9(1):2676. Epub 2018 Jul 11.

Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.

Although the amyloid β-protein (Aβ) is believed to play an initiating role in Alzheimer's disease (AD), the molecular characteristics of the key pathogenic Aβ forms are not well understood. As a result, it has proved difficult to identify optimal agents that target disease-relevant forms of Aβ. Here, we combined the use of Aβ-rich aqueous extracts of brain samples from AD patients as a source of human Aβ and live-cell imaging of iPSC-derived human neurons to develop a bioassay capable of quantifying the relative protective effects of multiple anti-Aβ antibodies. We report the characterization of 1C22, an aggregate-preferring murine anti-Aβ antibody, which better protects against forms of Aβ oligomers that are toxic to neurites than do the murine precursors of the clinical immunotherapeutics, bapineuzumab and solanezumab. These results suggest further examination of 1C22 is warranted, and that this bioassay maybe useful as a primary screen to identify yet more potent anti-Aβ therapeutics.
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http://dx.doi.org/10.1038/s41467-018-05068-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041266PMC
July 2018

MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways.

Acta Neuropathol 2018 10 7;136(4):537-555. Epub 2018 Jul 7.

Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Rd, 9006, Boston, MA, 02115, USA.

MicroRNAs (miRNA) regulate fundamental biological processes, including neuronal plasticity, stress response, and survival. Here, we describe a neuroprotective function of miR-132, the miRNA most significantly downregulated in neurons in Alzheimer's disease. We demonstrate that miR-132 protects primary mouse and human wild-type neurons and more vulnerable Tau-mutant neurons against amyloid β-peptide (Aβ) and glutamate excitotoxicity. It lowers the levels of total, phosphorylated, acetylated, and cleaved forms of Tau implicated in tauopathies, promotes neurite elongation and branching, and reduces neuronal death. Similarly, miR-132 attenuates PHF-Tau pathology and neurodegeneration, and enhances long-term potentiation in the P301S Tau transgenic mice. The neuroprotective effects are mediated by direct regulation of the Tau modifiers acetyltransferase EP300, kinase GSK3β, RNA-binding protein Rbfox1, and proteases Calpain 2 and Caspases 3/7. These data suggest miR-132 as a master regulator of neuronal health and indicate that miR-132 supplementation could be of therapeutic benefit for the treatment of Tau-associated neurodegenerative disorders.
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http://dx.doi.org/10.1007/s00401-018-1880-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132948PMC
October 2018
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