Decoding α-Synuclein-dependent mechanisms of amyloid-β-induced glial dysfunction in Alzheimer’s and Parkinson’s diseases

This project builds on a novel and potentially unifying discovery: the well-established synaptotoxic effects of amyloid-β (Aβ) require the presence of α-synuclein, a protein classically associated with Parkinson’s disease (PD). This finding offers a rare mechanistic link between the two most common neurodegenerative diseases, Alzheimer’s disease (AD) and PD, which have long been viewed as clinically and pathologically distinct. Given that Aβ also induces neuroinflammation and glial reactivity—and that α-synuclein is both expressed in and taken up by glial cells—the project sets out to investigate whether Aβ’s effects on astrocytes and microglia are likewise α-synuclein-dependent. This could reveal shared, targetable upstream mechanisms of neuroinflammatory dysfunction across disorders traditionally considered separate.
Aims and approach
The overarching aim is to dissect the molecular and cellular basis of Aβ-driven glial responses and determine how these are modulated by α-synuclein. The work will combine primary rodent models, human induced pluripotent stem cell (iPSC)-derived glia, and molecular tools to delineate causal pathways and pathological convergence.
Year 1 will establish whether Aβ-induced astrocytic and microglial phenotypes—such as morphological activation, altered phagocytosis, migratory behavior, and inflammatory marker expression—are dependent on α-synuclein. This will involve siRNA-mediated knockdown and extracellular immunosequestration of α-synuclein in primary rat glia, coupled with phenotypic analysis via super-resolution and high-content fluorescence microscopy, qPCR, and immunoblotting.
Year 2 will focus on identifying the specific forms of α-synuclein involved. Expression constructs and recombinant proteins—including wild-type, post-translationally modified, and familial PD mutant forms such as A53T—will be employed to define structure-function relationships in mediating Aβ-induced glial activation.
Year 3 will translate findings from rodent glia into human systems, using microglia and/or astrocytes differentiated from control human iPSCs to validate α-synuclein-dependent effects of Aβ in a human genetic background.
Year 4 will extend the model to disease-relevant settings, if time permits. iPSCs derived from AD and PD patients will be differentiated into glial cell types, allowing interrogation of whether α-synuclein-dependent Aβ effects observed in healthy cells are amplified or altered in a disease-specific context. This will inform the relevance of the mechanism to human pathophysiology and its potential as a cross-disease therapeutic target. This year will also include time for thesis write-up