α-Synuclein modulates tau spreading in mouse brains DOI Creative Commons

Fares Bassil,

Emily S. Meymand, Hannah J. Brown

et al.

The Journal of Experimental Medicine, Journal Year: 2020, Volume and Issue: 218(1)

Published: July 25, 2020

α-Synuclein (α-syn) and tau aggregates are the neuropathological hallmarks of Parkinson's disease (PD) Alzheimer's (AD), respectively, although both pathologies co-occur in patients with these diseases, suggesting possible crosstalk between them. To elucidate interactions pathological α-syn tau, we sought to model interactions. We show that increased accumulation occur following simultaneous introduction mousepreformed fibrils (mpffs) AD lysate-derived seeds (AD-tau) vitro vivo. Interestingly, absence endogenous mouse mice reduces spreading while did not affect seeding or capacity α-syn. These vivo results consistent our data wherein presence has no synergistic effects on Our point important role as a modulator pathology burden brains AD, PDD, DLB patients.

Language: Английский

Synergy between amyloid-β and tau in Alzheimer’s disease DOI
Marc Aurel Busche, Bradley T. Hyman

Nature Neuroscience, Journal Year: 2020, Volume and Issue: 23(10), P. 1183 - 1193

Published: Aug. 10, 2020

Language: Английский

Citations

869
Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis DOI
Phuong H. Nguyen, Ayyalusamy Ramamoorthy, Bikash R. Sahoo

et al.

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(4), P. 2545 - 2647

Published: Feb. 5, 2021

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural dynamic characterization all species along pathways from monomers to fibrils challenging by experimental computational means because they involve intrinsically disordered proteins most diseases. Yet understanding how amyloid become toxic challenge developing treatment for these Here we review what computer, vitro, vivo, pharmacological experiments tell us about accumulation deposition oligomers (Aβ, tau), α-synuclein, IAPP, superoxide dismutase 1 proteins, which have been mainstream concept underlying Alzheimer's disease (AD), Parkinson's (PD), type II diabetes (T2D), amyotrophic lateral sclerosis (ALS) research, respectively, years.

Language: Английский

Citations

545
Protein transmission in neurodegenerative disease DOI
Chao Peng, John Q. Trojanowski, Virginia M.‐Y. Lee

et al.

Nature Reviews Neurology, Journal Year: 2020, Volume and Issue: 16(4), P. 199 - 212

Published: March 23, 2020

Language: Английский

Citations

476
Prodromal Parkinson disease subtypes — key to understanding heterogeneity DOI
Daniela Berg, Per Borghammer, Seyed‐Mohammad Fereshtehnejad

et al.

Nature Reviews Neurology, Journal Year: 2021, Volume and Issue: 17(6), P. 349 - 361

Published: April 20, 2021

Language: Английский

Citations

276
Genetics and Pathogenesis of Parkinson's Syndrome DOI Creative Commons
Hui Ye, Laurie Robak, Meigen Yu

et al.

Annual Review of Pathology Mechanisms of Disease, Journal Year: 2022, Volume and Issue: 18(1), P. 95 - 121

Published: Sept. 13, 2022

Parkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected individual develops virtually unique form of syndrome. Clinical manifestations consist variable motor nonmotor features, myriad overlaps are recognized with other neurodegenerative conditions. Although most commonly characterized by alpha-synuclein protein pathology throughout the central peripheral nervous systems, distribution varies pathologies modify PD or trigger similar manifestations. Nearly all influenced. More than 100 genes genetic loci have been identified, cases likely arise from interactions among many common rare variants. Despite its complex architecture, insights experimental dissection coalesce reveal unifying biological themes, including synaptic, lysosomal, mitochondrial, andimmune-mediated mechanisms pathogenesis. This emerging understanding syndrome, coupled advances in biomarkers targeted therapies, presages successful precision medicine strategies.

Language: Английский

Citations

218
Biological aging processes underlying cognitive decline and neurodegenerative disease DOI Creative Commons
Mitzi M. Gonzales, Valentina R. Garbarino, Erin Pollet

et al.

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(10)

Published: May 15, 2022

Alzheimer's disease and related dementias (ADRD) are among the top contributors to disability mortality in later life. As with many chronic conditions, aging is single most influential factor development of ADRD. Even older adults who remain free dementia throughout their lives, cognitive decline neurodegenerative changes appreciable advancing age, suggesting shared pathophysiological mechanisms. In this Review, we provide an overview cognition, brain morphology, neuropathological protein accumulation across lifespan humans, complementary mechanistic evidence from animal models. Next, highlight selected processes that differentially regulated disease, including aberrant autophagy, mitochondrial dysfunction, cellular senescence, epigenetic changes, cerebrovascular inflammation, lipid dysregulation. We summarize research clinical translational studies link biological underlying ADRD pathogenesis. Targeting fundamental may represent a yet relatively unexplored avenue attenuate both age-related Collaboration fields geroscience neuroscience, coupled new models more closely align human processes, necessary advance novel therapeutic discovery realm.

Language: Английский

Citations

185
Microglia in the Neuroinflammatory Pathogenesis of Alzheimer’s Disease and Related Therapeutic Targets DOI Creative Commons

Yongle Cai,

Jingliu Liu,

Bin Wang

et al.

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: April 26, 2022

Alzheimer's disease (AD) is the most prevalent neurodegenerative worldwide, characterized by progressive neuron degeneration or loss due to excessive accumulation of β-amyloid (Aβ) peptides, formation neurofibrillary tangles (NFTs), and hyperphosphorylated tau. The treatment AD has been only partially successful as majority pharmacotherapies on market may alleviate some symptoms. In occurrence AD, increasing attention paid neurodegeneration, while resident glial cells, like microglia are also observed. Microglia, a kind crucial cells associated with innate immune response, functions double-edge sword role in CNS. They exert beneficial detrimental influence adjacent neurons through secretion both pro-inflammatory cytokines well neurotrophic factors. addition, their endocytosis debris toxic protein Aβ tau ensures homeostasis neuronal microenvironment. this review, we will systematically summarize recent research regarding roles pathology latest microglia-associated therapeutic targets mainly including genes, anti-inflammatory genes phagocytosis at length, which contradictory controversial warrant further be investigated.

Language: Английский

Citations

181
The human connectome in Alzheimer disease — relationship to biomarkers and genetics DOI
Meichen Yu, Olaf Sporns, Andrew J. Saykin

et al.

Nature Reviews Neurology, Journal Year: 2021, Volume and Issue: 17(9), P. 545 - 563

Published: July 20, 2021

Language: Английский

Citations

178
Amyloid β, Tau, and α-Synuclein aggregates in the pathogenesis, prognosis, and therapeutics for neurodegenerative diseases DOI Creative Commons
Urmi Sengupta, Rakez Kayed

Progress in Neurobiology, Journal Year: 2022, Volume and Issue: 214, P. 102270 - 102270

Published: April 18, 2022

Aggregation of specific proteins are histopathological hallmarks several neurodegenerative diseases, such as, Amyloid β (Aβ) plaques and tau neurofibrillary tangles in Alzheimer's disease (AD); morphologically different inclusions ratiometric 3 repeat (3 R) 4 (4 isoforms progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's (PiD); α-Synuclein (α-Syn) containing Lewy bodies (LBs) dystrophic neurites (LNs) Parkinson's (PD) dementia with (DLB). However, mixed brain protein pathologies have been frequently observed many these diseases normal aging brains, among which Aβ/tau tau/α-Syn crosstalks received increased attention. Interestingly, studies also shown synergistic interplay Aβ, tau, α-Syn suggesting a triumvirate. In this review, we summarize the emerging evidence aggregation pathophysiology, their overlap spectrum including AD, PSP, PiD, CBD, PD DLB. We discuss prognostic advancements made biomarker imaging techniques triumvirate proteinopathies. Finally, combined therapeutic modality involving biomarkers for future combinatorial immunotherapeutic targeting more than one aggregates. hope that multitarget approach will or additive effects to manage two might uncover promising strategy personalized combination therapies. Managing by optimizing diagnostic criteria correct immunotherapies be key factor success treatment.

Language: Английский

Citations

166
Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology DOI Creative Commons
Zoeb Jiwaji,

Sachin S. Tiwari,

Rolando Xavier Aviles‐Reyes

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Jan. 10, 2022

Abstract Alzheimer’s disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. TRAP-seq translatome analysis astrocytes in APP/PS1 ß-amyloidopathy MAPT P301S tauopathy mice revealed that only influenced expression AD risk genes, both pathologies precociously induced age-dependent changes, had distinct overlapping signatures found human post-mortem astrocytes. Both an astrocyte signature involving repression bioenergetic translation machinery, induction inflammation pathways plus protein degradation/proteostasis latter enriched targets inflammatory mediator Spi1 stress-activated cytoprotective Nrf2. Astrocyte-specific Nrf2 a reactive phenotype which recapitulated elements this proteostasis signature, reduced deposition phospho-tau accumulation their respective models, rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration behavioural/cognitive deficits. Thus, induce profiles associated with deleterious adaptive-protective signals, can slow patho-progression.

Language: Английский

Citations

165