Munc 18-1 is a multifaceted therapeutic target for dementia

Abstract

Dementia is a complex and multifactorial neurodegenerative condition, characterized by overlapping and interlinked pathophysiological implications including amyloid-β (Aβ) accumulation, Synaptic dysfunction, Lewy body formation, Tauopathy, neuroinflammation and oxidative stress. This complexity is one of the main reasons why single-target therapeutic strategies have largely failed to provide curative outcomes. As a result, there is a growing emphasis on identifying convergent molecular hubs that integrate multiple pathological pathways. In this context, Munc18-1 (STXBP1), a key regulator of synaptic vesicle exocytosis via SNARE complex assembly, has emerged as a central node connecting multiple facets of dementia pathology. Beyond its canonical role in neurotransmitter release, Munc18-1 influences amyloid precursor protein (APP) processing, modulates Tau phosphorylation through CDK5, and acts as a molecular chaperone for α-synuclein, thereby impacting amyloidogenic, Tauopathic, and Synucleinopathic pathways. Its dysfunction impairs synaptic integrity, disrupts BDNF signalling, and promotes neuroinflammatory responses through excitotoxicity and vesicle-mediated immune signalling. Notably, reductions or mutations in Munc18-1 have been consistently associated with cognitive decline in various dementia models. In the present article, we attempted to address that Munc18-1 could be a master regulator of multiple pathophysiologies associated with dementia and emerging therapeutic approaches that stabilize Munc18-1 and restore its multifaceted functions can be a novel strategy for the treatment of dementia.

Keywords: Amyloid precursor protein; Munc 18-1; Syntaxin-1; Tau; α-Synuclein.