CD2AP deficiency aggravates Alzheimer's disease phenotypes and pathology through p38 MAPK activation

Alzheimer's disease (AD) is the most common form of neurodegenerative disorder, which is characterized by a decline in cognitive abilities. Genome-wide association and clinicopathological studies have demonstrated that the CD2-associated protein (CD2AP) gene is one of the most important genetic risk factors for AD. However, the precise mechanisms by which CD2AP is linked to AD pathogenesis remain unclear.

The spatiotemporal expression pattern of CD2AP was determined. Then, we generated and characterized an APP/PS1 mouse model with neuron-specific Cd2ap deletion, using immunoblotting, immunofluorescence, enzyme-linked immunosorbent assay, electrophysiology and behavioral tests. Additionally, we established a stable CD2AP-knockdown SH-SY5Y cell line to further elucidate the specific molecular mechanisms by which CD2AP contributes to AD pathogenesis. Finally, the APP/PS1 mice with neuron-specific Cd2ap deletion were treated with an inhibitor targeting the pathway identified above to further validate our findings.

CD2AP is widely expressed in various regions of the mouse brain, with predominant expression in neurons and vascular endothelial cells. In APP/PS1 mice, neuronal knockout of Cd2ap significantly aggravated tau pathology, synaptic impairments and cognitive deficits. Mechanistically, the knockout of Cd2ap activated p38 mitogen-activated protein kinase (MAPK) signaling, which contributed to increased tau phosphorylation, synaptic injury, neuronal apoptosis and cognitive impairment. Furthermore, the phenotypes of neuronal Cd2ap knockout were ameliorated by a p38 MAPK inhibitor.

Our study presents the first in vivo evidence that CD2AP deficiency exacerbates the phenotypes and pathology of AD through the p38 MAPK pathway, identifying CD2AP/p38 MAPK as promising therapeutic targets for AD.