(Press-News.org) XIAMEN, China, 18 March 2025 – A groundbreaking peer-reviewed Thought Leaders Invited Review article in Brain Medicine (Genomic Press, New York) explores how CD2-associated protein (CD2AP) contributes to Alzheimer’s disease (AD), one of the most devastating neurodegenerative disorders affecting millions worldwide. CD2AP, initially identified for its role in cellular transport and cytoskeletal architecture, has now emerged as a crucial factor in AD pathology.
Genome-wide association studies (GWAS) have established CD2AP as a major genetic risk factor for late-onset Alzheimer’s disease (LOAD), with increasing evidence linking it to amyloid metabolism, tau pathology, synaptic integrity, and neuroinflammation.
“CD2AP is a fascinating molecule because it functions at the intersection of multiple pathways implicated in Alzheimer’s disease,” said Professor Yun-wu Zhang, corresponding author of the review. “By understanding its precise role in different brain cells, we may unlock new treatment strategies for this complex disorder.”
The Role of CD2AP in Amyloid-Beta Metabolism
Aβ accumulation and plaque formation are central to AD pathogenesis. CD2AP has been found to regulate Aβ metabolism by controlling the trafficking and degradation of amyloid precursor protein (APP). Studies show that CD2AP deficiency results in increased Aβ production and reduced clearance, accelerating plaque formation.
“CD2AP may play a dual role in amyloid regulation,” explained Professor Zhang. “On one hand, it limits excessive Aβ production, and on the other, it helps remove toxic amyloid aggregates. Disruptions in either function can tip the balance toward neurodegeneration.”
CD2AP and Synaptic Integrity: A Double-Edged Sword
Synapse loss is a strong predictor of cognitive decline in AD, and CD2AP is crucial for maintaining synaptic structure and function. However, the protein’s impact varies depending on the cell type. In neurons, CD2AP is essential for dendritic spine formation and stability, while in microglia, excessive CD2AP activity may promote pathological synapse pruning.
Recent studies indicate that loss of CD2AP in neurons leads to reduced spine density and impaired synaptic plasticity, key mechanisms underlying memory loss in AD.
“Neurons and microglia seem to have opposing needs when it comes to CD2AP,” said Mr. Yong Wang, co-author of the review. “In neurons, CD2AP is protective, but in microglia, too much CD2AP might actually worsen synapse loss. This makes it a challenging but exciting therapeutic target.”
Neuroinflammation and CD2AP: The Microglial Connection
Microglial activation is a hallmark of AD, and CD2AP plays a key role in modulating microglial responses to amyloid plaques. The review highlights that CD2AP-deficient microglia exhibit reduced phagocytosis, leading to increased amyloid burden. However, excessive CD2AP activity in microglia is linked to heightened synaptic pruning and inflammation, potentially worsening neurodegeneration.
“Microglial CD2AP levels need to be carefully balanced,” said Mr. Wang. “Too little CD2AP results in inefficient amyloid clearance, while too much may contribute to neuroinflammation and synaptic loss.”
CD2AP and Tau Pathology
Beyond its role in amyloid regulation, CD2AP has been implicated in tau-mediated neurotoxicity. Tau tangles, another defining feature of AD, disrupt neuronal function and contribute to cognitive impairment. Studies show that certain CD2AP variants are associated with increased tau phosphorylation, which exacerbates neuronal damage.
“This is an area that requires further investigation,” Mr. Wang added. “Understanding how CD2AP influences tau pathology could provide a missing link between amyloid and tau dysfunction in Alzheimer’s disease.”
Implications for Future Alzheimer’s Treatments
Given its wide-ranging effects, CD2AP presents a unique opportunity for therapeutic intervention. However, its cell type-specific roles complicate drug development. Researchers are now exploring whether targeting CD2AP in a way that enhances neuronal protection while limiting microglial overactivation could be a viable treatment strategy.
“We are just beginning to understand how CD2AP functions across different cell types,” said Professor Zhang. “Our goal is to develop precision therapies that can modulate CD2AP activity in a way that benefits patients without causing unintended consequences.”
Key Questions Moving Forward
Could CD2AP modulation serve as a novel therapeutic strategy for AD?
How can researchers selectively target CD2AP in neurons versus microglia?
What role does CD2AP play in early-stage AD, and could it serve as a biomarker for disease progression?
The peer-reviewed Thought Leaders Invited Review article, “CD2AP in Alzheimer’s disease: Key mechanisms and therapeutic potential,” appears online on 18 March 2025 in Brain Medicine (Genomic Press) and is freely accessible at https://doi.org/10.61373/bm025i.0026.
About Brain Medicine: Brain Medicine (ISSN: 2997-2639) is a peer-reviewed medical research journal published by Genomic Press, New York. Brain Medicine is a new home for the cross-disciplinary pathway from innovation in fundamental neuroscience to translational initiatives in brain medicine. The journal’s scope includes the underlying science, causes, outcomes, treatments, and societal impact of brain disorders across all clinical disciplines and their interface.
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