PCSK9 Links Metabolic Dysfunction to Alzheimer's Neurodegeneration, Suggesting New Therapeutic Target

Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a significant mediator linking metabolic dysfunction to Alzheimer's disease (AD) neurodegeneration. While well-known for systemic cholesterol homeostasis, its function in the central nervous system (CNS) is less understood. Elevated PCSK9 activity may degrade crucial neuronal receptors like LDL receptor-related protein-1 (LRP-1) and low-density lipoprotein receptor (LDLR), which are vital for amyloid-β (Aβ) clearance and neuronal survival. This degradation leads to Aβ deposition and reduced neuronal cholesterol uptake, contributing to neurotoxicity and neuronal dysfunction.

This review synthesized existing literature to explore the multifaceted role of PCSK9 in the development and exacerbation of Alzheimer's disease (AD). The authors systematically examined how elevated PCSK9 levels contribute to AD pathogenesis through various molecular mechanisms. They investigated its involvement in disrupting brain cholesterol homeostasis, glucose dysregulation, mTOR dysregulation, increased oxidative stress, neuroinflammation, reduced neurogenesis, and affected Wnt-β-catenin and cholinergic signaling pathways. The overarching aim was to establish PCSK9 as a significant mediator bridging metabolic dysfunction and neurodegeneration, thereby identifying it as a promising therapeutic target for AD.

The review highlights that PCSK9 significantly disrupts brain cholesterol homeostasis and uptake by promoting the degradation of key neuronal receptors, specifically LDL receptor-related protein-1 (LRP-1) and low-density lipoprotein receptor (LDLR). These receptors are crucial for the clearance of amyloid-β (Aβ) and maintaining neuronal health. Their degradation by PCSK9 leads to increased Aβ deposition near synapses and reduced cholesterol uptake by neurons, directly contributing to neurotoxicity and neuronal dysfunction. Beyond cholesterol, PCSK9 is implicated in a cascade of AD-relevant pathological processes, including glucose dysregulation, mechanistic target of rapamycin (mTOR) dysregulation, increased oxidative stress, neuroinflammation, reduced neurogenesis, and impaired Wnt-β-catenin and cholinergic signaling.

Preclinical studies consistently demonstrate that pharmacological therapies targeting PCSK9 can yield promising results by reducing neuroinflammation, modulating lipid homeostasis, and lowering Aβ accumulation. Collectively, these findings underscore that PCSK9's involvement in multiple interconnected molecular mechanisms significantly contributes to AD progression.