The Ubiquitin System in Alzheimer’s Disease

Harris, Lee D.; Jasem, Sarah; Licchesi, Julien

doi:10.1007/978-3-030-38266-7_8

Cited by 52 publications

(35 citation statements)

References 295 publications

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“…It has been shown that soluble Aβ oligomers promote AMPAR internalization and degradation ( Guntupalli et al., 2017 ; Miñano-Molina et al., 2011 ). This is consistent with studies of our own, and those of others, which show an increase in ubiquitination of AMPARs in AD ( Guntupalli et al., 2017 ; Rodrigues et al., 2016 ; Zhang et al., 2018 ) (as reviewed by Harris et al, 2020 ; Moraes et al., 2020 ; Zhu and Tsai, 2020 ). Findings from our recent work have revealed for the first time that AMPARs are also subject to acetylation, a new form of AMPAR regulation that antagonizes receptor ubiquitination due to competition for the same lysine residues ( Wang et al., 2017 ).…”

Section: Discussionsupporting

confidence: 94%

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

et al. 2020

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Summary In Alzheimer's disease (AD), decreases in the amount and synaptic localization of AMPA receptors (AMPARs) result in weakened synaptic activity and dysfunction in synaptic plasticity, leading to impairments in cognitive functions. We have previously found that AMPARs are subject to lysine acetylation, resulting in higher AMPAR stability and protein accumulation. Here we report that AMPAR acetylation was significantly reduced in AD and neurons with Aβ incubation. We identified p300 as the acetyltransferase responsible for AMPAR acetylation and found that enhancing GluA1 acetylation ameliorated Aβ-induced reductions in total and cell-surface AMPARs. Importantly, expression of acetylation mimetic GluA1 (GluA1-4KQ) in APP/PS1 mice rescued impairments in synaptic plasticity and memory. These findings indicate that Aβ-induced reduction in AMPAR acetylation and stability contributes to synaptopathy and memory deficiency in AD, suggesting that AMPAR acetylation may be an effective molecular target for AD therapeutics.

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Section: Discussionsupporting

confidence: 94%

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

et al. 2020

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“…Of interest, SDF-1α as well as other endogenous CXCR4 ligands, including ubiquitin and macrophage migration inhibitory factor (MIF) have been shown to be increased in AD brain tissue particularly around plaques, co-localizing with dystrophic neurons and within murine DAM populations 61 – 64 . This further highlights the need for exploration of the role of CXCR4 in microglial migration in disease particularly as a potential therapeutic for patients with mutations in TREM2.…”

Section: Discussionmentioning

confidence: 99%

Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer’s disease

et al. 2020

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The discovery of TREM2 as a myeloid-specific Alzheimer’s disease (AD) risk gene has accelerated research into the role of microglia in AD. While TREM2 mouse models have provided critical insight, the normal and disease-associated functions of TREM2 in human microglia remain unclear. To examine this question, we profile microglia differentiated from isogenic, CRISPR-modified TREM2-knockout induced pluripotent stem cell (iPSC) lines. By combining transcriptomic and functional analyses with a chimeric AD mouse model, we find that TREM2 deletion reduces microglial survival, impairs phagocytosis of key substrates including APOE, and inhibits SDF-1α/CXCR4-mediated chemotaxis, culminating in an impaired response to beta-amyloid plaques in vivo. Single-cell sequencing of xenotransplanted human microglia further highlights a loss of disease-associated microglial (DAM) responses in human TREM2 knockout microglia that we validate by flow cytometry and immunohistochemistry. Taken together, these studies reveal both conserved and novel aspects of human TREM2 biology that likely play critical roles in the development and progression of AD.

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“…Additionally, microglia and other immune cells have been shown to provoke a neuroinflammatory response and assist with the clearance of amyloid plaques via phagocytosis (Fang et al, 2010;Tarasoff-Conway et al, 2015). Furthermore, alterations in the intracellular degradation of Aβ 1−40 by endo-lysosomal compartments, which involves the ubiquitin-E3 ligase pathway, may also be affected in AD patients (Tarasoff-Conway et al, 2015;Harris et al, 2020). Alternatively, Aβ may be transported between the ISF and the systemic circulation by transendothelial active transport, assisted by various mediators including p-glycoprotein 1, LRP1, RAGE, alpha2-macroglobulin, clusterin, and apolipoprotein J (Tarasoff-Conway et al, 2015; Reed et al, 2019).…”

Section: Discussion and Clinical Significancementioning

confidence: 99%

The Role of Basement Membranes in Cerebral Amyloid Angiopathy

2020

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Dementia is a neuropsychiatric syndrome characterized by cognitive decline in multiple domains, often leading to functional impairment in activities of daily living, disability, and death. The most common causes of age-related progressive dementia include Alzheimer’s disease (AD) and vascular cognitive impairment (VCI), however, mixed disease pathologies commonly occur, as epitomized by a type of small vessel pathology called cerebral amyloid angiopathy (CAA). In CAA patients, the small vessels of the brain become hardened and vulnerable to rupture, leading to impaired neurovascular coupling, multiple microhemorrhage, microinfarction, neurological emergencies, and cognitive decline across multiple functional domains. While the pathogenesis of CAA is not well understood, it has long been thought to be initiated in thickened basement membrane (BM) segments, which contain abnormal protein deposits and amyloid-β (Aβ). Recent advances in our understanding of CAA pathogenesis link BM remodeling to functional impairment of perivascular transport pathways that are key to removing Aβ from the brain. Dysregulation of this process may drive CAA pathogenesis and provides an important link between vascular risk factors and disease phenotype. The present review summarizes how the structure and composition of the BM allows for perivascular transport pathways to operate in the healthy brain, and then outlines multiple mechanisms by which specific dementia risk factors may promote dysfunction of perivascular transport pathways and increase Aβ deposition during CAA pathogenesis. A better understanding of how BM remodeling alters perivascular transport could lead to novel diagnostic and therapeutic strategies for CAA patients.

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The Ubiquitin System in Alzheimer’s Disease

Cited by 52 publications

References 295 publications

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer’s disease

The Role of Basement Membranes in Cerebral Amyloid Angiopathy

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