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Abbasi A A, Fereidouni A, Moradikor N. LRP1 and Microglial Dysfunction in Alzheimer’s Disease: Mechanistic Crosstalk, Dual-Target Therapeutic Strategies, and Sleep-Oriented Adjunctive Approaches. Neuroscience Updates 2025; 3 (1) :101-115
URL: http://neuroupdates.de/article-1-129-en.html
LRP1 and Microglial Dysfunction in Alzheimer’s Disease: Mechanistic Crosstalk, Dual-Target Therapeutic Strategies, and Sleep-Oriented Adjunctive Approaches
Adeel Ahmed Abbasi1 , Ali Fereidouni1 , Nasrollah Moradikor *1
1- International Center for Neuroscience Research, Institute for Intelligent Research, Tbilisi, Georgia
Abstract:   (73 Views)

A progressive decline in cognitive ability characterizes Alzheimer’s Disease (AD) as a result of the deposition of amyloid-β (Aβ) and persistent neuroinflammatory response. A significant contributor involved in these changes is the low-density lipoprotein receptor-related protein 1 (LRP1). It is a key mediator of Aβ clearance, and its downregulation with age and disease hastens amyloid accumulation. In chronic exposure to Aβ, in the end, leads to the formation of a microglial senescence-associated secretory phenotype SASP associated with inflammation, a loss of phagocytosis, and lysosomal dysfunction. Enhanced intracellular protein accumulation caused by dysfunctional microglia worsens neurodegenerative progression by impairing chaperone-mediated autophagy (CMA). This research examines the neurodegenerative crosstalk of the LRP1–Aβ–Microglia axis. This approach presents an innovative solution to dual-target therapy by combining CAR-transcriptionally modified microglia to boost extracellular Aβ clearance and enhance intracellular proteolytic pathways, specifically LRP1 and CMA. This strategy aims to relieve the burden of amyloid burden, restore homeostasis, and reduce pathogenic inflammation by combining receptor-mediated clearance with engineered phagocytic activity. Moreover, available literature is discussed about glymphatic dysfunctions and microglial dysregulation, their relation to sleep disturbances, and the potential of sleep-supportive therapies such as sake yeast sleep-supporting supplements as adjunct therapies to enhance cognitive resilience in Alzheimer’s Disease (AD). Integrating these mechanistic insights with progress in therapeutics emphasizes the multifaceted approaches to mitigating the impacts of Alzheimer's disease pathology.

Keywords: Alzheimer’s disease, LRP1, Microglial dysfunction, Amyloid‐β clearance, CAR-microglia, Neuroinflammation
     
Type of Study: Review Article | Subject: Neurodegenerative Disease
Received: 2025/08/25 | Accepted: 2025/10/15 | Published: 2025/10/25
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