Deciphering Synaptic Vulnerability in Alzheimer's: A Proteomic Approach

Neurodegenerative diseases like Alzheimer's disease (AD) are characterized by progressive synaptic loss and cognitive decline. Understanding the molecular underpinnings of synaptic vulnerability in AD is crucial for developing effective therapies. This study aimed to elucidate the proteomic changes associated with synaptic degeneration in the AD brain. We utilized a mass spectrometry-based proteomic approach on post-mortem brain tissues from AD patients and age-matched controls. A total of 1,200 proteins were identified, with 150 exhibiting significant changes in expression (p < 0.05). Notably, proteins involved in synaptic vesicle cycling and energy metabolism, such as synaptotagmin and ATP synthase, were markedly downregulated in AD samples. Additionally, pathway analysis revealed a significant disruption in the mitochondrial respiratory chain, highlighting its potential role in synaptic dysfunction. Our findings suggest that impaired synaptic vesicle dynamics and mitochondrial dysfunction are central to synaptic vulnerability in AD. These insights could pave the way for novel therapeutic targets aimed at preserving synaptic integrity in neurodegenerative conditions.