Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer’s disease pathology

Cell, Journal Year: 2023, Volume and Issue: 186(20), P. 4365 - 4385.e27

Published: Sept. 1, 2023

Alzheimer's disease (AD) is the most common cause of dementia worldwide, but molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. To address this, we generated a single-cell transcriptomic atlas aged human prefrontal cortex covering 2.3 million cells from postmortem brain samples 427 individuals with varying degrees AD pathology impairment. Our analyses identified AD-pathology-associated alterations shared between excitatory neuron subtypes, revealed coordinated increase cohesin complex DNA damage response factors in neurons oligodendrocytes, uncovered genes pathways associated high function, dementia, resilience to pathology. Furthermore, selectively vulnerable somatostatin inhibitory subtypes depleted AD, discovered two distinct groups that were more abundant preserved function late life, link

Language: Английский

---

Integrated multimodal cell atlas of Alzheimer’s disease

Nature Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 14, 2024

Alzheimer's disease (AD) is the leading cause of dementia in older adults. Although AD progression characterized by stereotyped accumulation proteinopathies, affected cellular populations remain understudied. Here we use multiomics, spatial genomics and reference atlases from BRAIN Initiative to study middle temporal gyrus cell types 84 donors with varying pathologies. This cohort includes 33 male 51 female donors, an average age at time death 88 years. We used quantitative neuropathology place along a pseudoprogression score. Pseudoprogression analysis revealed two phases: early phase slow increase pathology, presence inflammatory microglia, reactive astrocytes, loss somatostatin

Language: Английский

---

Molecular and cellular mechanisms of selective vulnerability in neurodegenerative diseases

Nature reviews. Neuroscience, Journal Year: 2024, Volume and Issue: 25(5), P. 351 - 371

Published: April 4, 2024

Language: Английский

---

Integrated multimodal cell atlas of Alzheimer’s disease

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: May 23, 2023

Alzheimer's disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive stereotyped accumulation protein aggregates, but underlying molecular cellular mechanisms driving AD progression vulnerable cell populations affected by remain coarsely understood. The current study harnesses single spatial genomics tools knowledge from BRAIN Initiative Cell Census Network to understand impact on middle temporal gyrus types. We used image-based quantitative neuropathology place 84 donors spanning spectrum pathology along continuous pseudoprogression score multiomic technologies profile nuclei each donor, mapping their transcriptomes, epigenomes, coordinates type reference with unprecedented resolution. Temporal analysis cell-type proportions indicated an early reduction Somatostatin-expressing neuronal subtypes late decrease supragranular intratelencephalic-projecting excitatory Parvalbumin-expressing neurons, increases disease-associated microglial astrocytic states. found complex gene expression differences, ranging global type-specific effects. These effects showed different patterns indicating diverse perturbations as function progression. A subset particularly severe phenotype, which correlated steeper cognitive decline. created freely available public resource explore these data accelerate progress research at SEA-AD.org.

Language: Английский

---

The Amyloid-Beta Clearance: From Molecular Targets to Glial and Neural Cells

Biomolecules, Journal Year: 2023, Volume and Issue: 13(2), P. 313 - 313

Published: Feb. 7, 2023

The deposition of amyloid-beta (Aβ) plaques in the brain is one primary pathological characteristics Alzheimer’s disease (AD). It can take place 20–30 years before onset clinical symptoms. imbalance between production and clearance Aβ major causes AD. Enhancing at an early stage attractive preventive therapeutic strategy Direct inhibition aggregation using small molecules, peptides, monoclonal antibody drugs has not yielded satisfactory efficacy trials for decades. Novel approaches are required to understand combat deposition. Neurological dysfunction a complex process that integrates functions different types cells brain. role non-neurons AD been fully elucidated. An in-depth understanding interactions neurons contribute elucidation formation identification effective drug targets. patient-derived pluripotent stem (PSCs) contain complete background information have potential differentiate into various vitro, which may bring new insight treatment Here, we systematically review latest studies on clarify roles cell among microglia, astroglia response plaques, will be beneficial explore methods reconstructing models inducible PSCs (iPSCs) through differentiation techniques validating applications plaques. This provide most promising directions finding clues preventing delaying development

Language: Английский

---

Integrated multimodal cell atlas of Alzheimer’s disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: May 9, 2023

Abstract Alzheimer’s disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive stereotyped accumulation protein aggregates, but underlying molecular cellular mechanisms driving AD progression vulnerable cell populations affected by remain coarsely understood. The current study harnesses single spatial genomics tools knowledge from BRAIN Initiative Cell Census Network to understand impact on middle temporal gyrus types. We used image-based quantitative neuropathology place 84 donors spanning spectrum pathology along continuous pseudoprogression score multiomic technologies profile nuclei each donor, mapping their transcriptomes, epigenomes, coordinates type reference with unprecedented resolution. Temporal analysis cell-type proportions indicated an early reduction Somatostatin-expressing neuronal subtypes late decrease supragranular intratelencephalic-projecting excitatory Parvalbumin-expressing neurons, increases disease-associated microglial astrocytic states. found complex gene expression differences, ranging global type-specific effects. These effects showed different patterns indicating diverse perturbations as function progression. A subset particularly severe phenotype, which correlated steeper cognitive decline. created freely available public resource explore these data accelerate progress research at SEA-AD.org .

Language: Английский

---

Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics

Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

---

Genome‐wide methylomic regulation of multiscale gene networks in Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 19(8), P. 3472 - 3495

Published: Feb. 22, 2023

Recent studies revealed the association of abnormal methylomic changes with Alzheimer's disease (AD) but there is a lack systematic study impact alterations over molecular networks underlying AD.

Language: Английский

---

Interrogation of the human cortical peptidome uncovers cell-type specific signatures of cognitive resilience against Alzheimer’s disease

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: March 26, 2024

Abstract Alzheimer’s disease (AD) is characterised by age-related cognitive decline. Brain accumulation of amyloid-β plaques and tau tangles required for a neuropathological AD diagnosis, yet up to one-third AD-pathology positive community-dwelling elderly adults experience no symptoms decline during life. Conversely, some exhibit chronic impairment in absence measurable neuropathology, prompting interest into resilience—retained cognition despite significant neuropathology—and frailty—impaired low neuropathology. Synapse loss widespread within the AD-dementia, but not AD-resilient, brain. Recent evidence points towards critical roles synaptic proteins, such as neurosecretory VGF, resilience. However, VGF related proteins often signal peptide derivatives. Here, nontryptic peptidomic mass spectrometry was performed on 102 post-mortem cortical samples from individuals across spectra. Neuropeptide signalling proteoforms derived somatostatin (SST) protachykinin-1 (TAC1) showed higher abundance AD-resilient than AD-dementia brain, whereas cholecystokinin (CCK) chromogranin (CHG) A/B multiple cytoskeletal molecules were enriched frail vs control Integrating our data with publicly available single nuclear RNA sequencing (snRNA-seq) enrichment cognition-related genes defined cell-types established links resilience, including SST interneurons excitatory intratelencephalic cells.

Language: Английский

---

Detecting the effect of genetic diversity on brain composition in an Alzheimer’s disease mouse model

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: May 20, 2024

Alzheimer's disease (AD) is broadly characterized by neurodegeneration, pathology accumulation, and cognitive decline. There considerable variation in the progression of clinical symptoms humans, highlighting importance genetic diversity study AD. To address this, we analyze cell composition amyloid-beta deposition 6- 14-month-old AD-BXD mouse brains. We utilize analytical QUINT workflow- a suite software designed to support atlas-based quantification, which expand deliver highly effective method for registering quantifying changes diverse models. In applying expanded workflow, quantify near-global age-related increases microglia, astrocytes, amyloid-beta, identify strain-specific regional neuron load. understand how individual differences affect interpretation bulk gene expression AD, combine hippocampal immunohistochemistry analyses with RNA-sequencing data. This approach allows us categorize genes whose response AD and/or load-dependent manner. Ultimately, our demonstrates use workflow standardize quantification data mice, - providing valuable insights into cellular load amyloid model.

Language: Английский

---