en Neurodegenerative Disease Neurodegenerative Disease Review Article <h4 style="text-align: justify;"><span style="line-height:2;"><span style="font-size:14px;"><span style="font-family:Tahoma;"><span style="color:#212121">A progressive decline in cognitive ability characterizes Alzheimer&rsquo;s Disease (AD) as a result of the deposition of amyloid-&beta; (A&beta;) 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 A&beta; clearance, and its downregulation with age and disease hastens amyloid accumulation. In chronic exposure to A&beta;, in the end, leads to the formation of a microglial </span>senescence-associated secretory phenotype <span style="color:#212121">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&ndash;A&beta;&ndash;Microglia axis. This approach presents an innovative solution to dual-target therapy by combining <span style="background:yellow"><span style="background-color:#ffffff;">CAR</span></span>-transcriptionally modified microglia to boost extracellular A&beta; 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&rsquo;s Disease (AD). Integrating these mechanistic insights with progress in therapeutics emphasizes the multifaceted approaches to mitigating the impacts of Alzheimer&#39;s disease pathology.</span></span></span></span></h4> Alzheimer’s disease, LRP1, Microglial dysfunction, Amyloid‐β clearance, CAR-microglia, Neuroinflammation 101 115 http://neuroupdates.de/browse.php?a_code=A-10-1-61&slc_lang=en&sid=1 Adeel Ahmed Abbasi 1003194753284600462 0009-0001-7926-4927 No International Center for Neuroscience Research, Institute for Intelligent Research, Tbilisi, Georgia Ali Fereidouni 1003194753284600463 1003194753284600463 No International Center for Neuroscience Research, Institute for Intelligent Research, Tbilisi, Georgia Nasrollah Moradikor moradikor@neuroscience.edu.ge 1003194753284600464 1003194753284600464 Yes International Center for Neuroscience Research, Institute for Intelligent Research, Tbilisi, Georgia