Microglia in Alzheimer's Disease: An Unprecedented Opportunity as Prospective Drug Target.
Bhargavi KulkarniNatália Cruz MartinsDileep KumarPublished in: Molecular neurobiology (2022)
Alzheimer's disease (AD) is an ever more common neurodegenerative disease among the elderly, characterized by recurrent neuroinflammation and amyloid beta (Aβ) accumulation in the brain parenchyma. Recent genome-wide association studies (GWAS) have shown a distinct role for the innate immune system in AD, with microglia playing a key role. The function of microglial cells is stringently regulated by the neighboring microenvironment in the brain. Upon interruption in diseases, like AD, it demonstrates neurotoxic and neuroprotective action by M1 (neurotoxic) and M2 (neuroprotective) microglial phenotypes, respectively, in the brain. Microglial cells on activation by complement factors, toll-like receptors, and genetic variants result in Aβ' phagocytosis, synaptic pruning, and reactivation of complement pathway. Recent studies have demonstrated the presence of potential therapeutic targets in microglial cells. Immune receptors revealed on microglia as potential drug targets can be paired immunoglobulin-like type 2 receptor (PILR), CD3358, and triggering receptor expressed on myeloid cells 2 (TREM2), as they can have impact on late-onset AD occurrence and progression. Thus, targeting these receptors can accentuate the beneficial effects of microglial cells required to decelerate the progression of AD. This review emphasizes the microglial phenotypes, its function in AD brain, and potential immunological and therapeutic targets to fight this highly progressive neurodegenerative disorder.
Keyphrases
- induced apoptosis
- inflammatory response
- cell cycle arrest
- lipopolysaccharide induced
- neuropathic pain
- late onset
- lps induced
- cerebral ischemia
- white matter
- endoplasmic reticulum stress
- stem cells
- resting state
- signaling pathway
- risk assessment
- cell death
- traumatic brain injury
- spinal cord injury
- spinal cord
- adverse drug
- climate change
- functional connectivity
- bone marrow
- pi k akt
- drug delivery
- subarachnoid hemorrhage
- drug induced
- case control
- electronic health record