Advances in Pharmacology and Pharmacy Vol. 13(2), pp. 230 - 237
DOI: 10.13189/app.2025.130207
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Role of PCSK9 in Alzheimer's Disease by Modulating Brain Cholesterol Homeostasis: An Overview


Priyanka Arya 1,*, Vikram Sharma 1, Rahul Sagar 2, Surabhi Thapliyal 3
1 Galgotias College of Pharmacy, Greater Noida, India
2 AnovIP, New Delhi, 110049, India
3 Department of Pharmacology, All India Institute of Medical Sciences, Rishikesh 249203, India

ABSTRACT

Impaired brain cholesterol homeostasis has been implicated in the development and progression of Alzheimer's disease (AD). Cholesterol is crucial for various neuronal functions, including synapse formation, neurotransmitter release, and membrane fluidity. Disruptions in cholesterol metabolism can lead to the accumulation of toxic proteins such as beta-amyloid and tau, which are hallmarks of AD pathology. Proprotein convertase subtilisin/kexin type 9 (PCSK9) was initially discovered in the brain, suggesting it may play a role in brain development and cell death. While its exact function in the nervous system and the progression of Alzheimer's disease (AD) remains unclear, PCSK9 is believed to affect neuronal and lipid receptors, such as low-density lipoprotein receptors (LDLR), LDL receptor-related protein 1 (LRP1), and apolipoprotein E (APOE). These effects can lead to decreased cholesterol uptake by neurons and glial cells, disrupting cellular functions and potentially contributing to neurodegeneration and the development of AD. Studies have shown that PCSK9 levels are elevated in the cerebrospinal fluid (CSF) of individuals with AD, suggesting a potential association between PCSK9 and AD pathogenesis. Additionally, evidence highlights that treatment with PCSK9 inhibitors like alirocumab and evolocumab reduces dendritic spine loss via reduction of microglial, astrocytic activation and amyloid β aggregation. Overall, while the exact mechanisms by which PCSK9 influences brain cholesterol homeostasis in AD are still being elucidated, accumulating evidence suggests that PCSK9 may play a role in this process and could represent a potential therapeutic target for AD. Therefore, the present review sheds light on the PCSK9 potential role in the pathogenesis of AD by modulating brain cholesterol homeostasis.

KEYWORDS
Proprotein Convertase Subtilisin/Kexin Type 9, Alzheimer's Disease, Cholesterol, Cerebrospinal Fluid, Low Density Lipoprotein Receptor, Astrocyte, Glial, Neuroinflammation

Cite This Paper in IEEE or APA Citation Styles
(a). IEEE Format:
[1] Priyanka Arya , Vikram Sharma , Rahul Sagar , Surabhi Thapliyal , "Role of PCSK9 in Alzheimer's Disease by Modulating Brain Cholesterol Homeostasis: An Overview," Advances in Pharmacology and Pharmacy, Vol. 13, No. 2, pp. 230 - 237, 2025. DOI: 10.13189/app.2025.130207.

(b). APA Format:
Priyanka Arya , Vikram Sharma , Rahul Sagar , Surabhi Thapliyal (2025). Role of PCSK9 in Alzheimer's Disease by Modulating Brain Cholesterol Homeostasis: An Overview. Advances in Pharmacology and Pharmacy, 13(2), 230 - 237. DOI: 10.13189/app.2025.130207.