Biology subjects

Chakrabaty, P.

Publications and source records attributed to Chakrabaty, P..

3 recordsLinked to original sources

bioRxiv2024

Human APOE allelic variants suppress the formation of diffuse and fibrillar Aβ deposits relative to mouse Apoe in transgenic mouse models of Alzheimer amyloidosis

BackgroundApolipoprotein E (apoE) modulates the deposition of amyloid {beta} (A{beta}) aggregates in Alzheimers disease (AD) in an isoform-dependent manner. In transgenic mouse models of AD-amyloidosis, replacing mouse Apoe alleles with human APOE variants suppresses fibrillar A{beta} deposits. In the PD-APP transgenic mouse model, deletion of the Apoe gene led to selective reduction of fibrillar deposits with increased diffuse deposits. This finding suggested that apoE may have differential effects on different types of amyloid pathology. MethodsHere, we investigated the interaction between the type of A{beta} pathology in the brain and human apoE isoforms in different transgenic mouse models. ResultsIn the APPsi model that develops predominantly diffuse A{beta} plaques late in life, we determined that replacing mouse Apoe with human APOE3 or APOE4 genes potently suppressed diffuse amyloid formation, with apoE3 exhibiting a greater activity relative to apoE4. Relative to apoE4, apoE3 appeared to suppress A{beta} deposition in the cerebral vasculature. In a second cohort, we accelerated the deposition of diffuse A{beta} pathology by seeding, finding that seeded APPsi mice harboring APOE4 or APOE3 developed equal burdens of diffuse parenchymal A{beta}. Finally, in the recently developed SAA-APP model that has a mix of dense-core and fibrous A{beta} plaques, we found that replacing mouse apoE with human apoE suppressed deposition significantly, with the amyloid burden following the trend of Apoe>>APOE4> APOE3[~]APOE2. In the SAA-APP and seeded APPsi models, we found evidence of apoE protein associated with A{beta} plaques. ConclusionsOverall, these observations demonstrate a capacity for human apoE to suppress the deposition of both diffuse and fibrillar-cored deposits, relative to mouse apoE. Notably, in the seeded paradigm, the suppressive activity of human apoE3 and apoE4 appeared to be overwhelmed. Taken together, this study demonstrates that APOE genotype influences the deposition of both cored-fibrillar and diffuse amyloid.

neuroscience↗

bioRxiv2018

Alzheimer’s disease Phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph

Recent Genome Wide Association Studies (GWAS) have identified novel rare coding variants in immune genes associated with late onset AD (LOAD). Amongst these, a polymorphism in Phospholipase C-gamma 2 (PLCG2) P522R, has been reported to be protective against LOAD. PLC enzymes are key elements in signal transmission networks and are potentially druggable targets. PLCG2 is highly expressed in the hematopoietic system. Hypermorphic mutations in PLCG2 in humans have been reported to cause autoinflammation and immune disorders, suggesting a key role for this enzyme in the regulation of immune cell function.\n\nWe confirmed that PLCG2 expression is restricted primarily to microglia in both the healthy and AD brain. Functional analysis of the P522R variant in heterologous systems demonstrated a small hypermorphic effect of the mutation on enzyme function. PLC{gamma}2 is therefore a potential target for modulating microglia function in AD, and a small molecule drug that weakly activates PLC{gamma}2 may be one potential therapeutic approach.\n\nSUMMARYThe PLCG2 P522R variant is protective against Alzheimers disease (AD). We show that PLCG2 is expressed in CNS-resident myeloid cells, and the P522R polymorphism weakly activates enzyme function. These data suggest that activation of PLCG2 and not inhibition could be therapeutically beneficial in AD.

neuroscience↗

bioRxiv2018

High affinity interactions and signal transduction between Aβ oligomers and TREM2

Rare coding variant in the Triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased risk for Alzheimers disease (AD), but how they confer this risk remains uncertain. We assessed binding of TREM2, AD associated TREM2 variants to various forms of A{beta} and APOE in multiple assays. TREM2 interacts directly with various forms of A{beta}, with highest affinity interactions observed between TREM2 and soluble A{beta}42 oligomers. We confirm the previous interaction between APOE3 and APOE4 and TREM2. High affinity binding of TREM2 to A{beta} oligomers is characterized by very slow dissociation. Pre-incubation with A{beta} is shown to block the interaction of APOE. In cellular assays, AD-associated variants of TREM2 reduced the amount of A{beta}42 internalized, and in NFAT assay the R47H variant decreased NFAT signaling activity in response to A{beta}42. These studies demonstrate i) a high affinity interaction between TREM2 and A{beta} oligomers that can block interaction with another ligand and ii) that AD-associated TREM2 variants bind A{beta} with equivalent affinity but show loss of function in terms of signaling and A{beta} internalization.

cell biology↗