Therapeutic Targeting of TREM2 for Alzheimer's Disease

Despite numerous promising therapeutic approaches identified pre-clinically to treat Alzheimer¡¦s disease, the translation of these therapies to the clinic have been incredibly disappointing. Therefore, the identification of novel therapeutic targets is necessary to reach the goal of the National Alzheimer¡¦s Project Act (NAPA) of having an effective treatment in place by 2025. With the many genome-wide association studies (GWAS) that have been performed for AD, we may be able to identify novel therapeutic targets based on the risk genes identified. One of the genes that has a strong effect on AD risk is the TREM2 gene. TREM2, the triggering receptor expressed on myeloid cells-2, is an innate immune receptor expressed on microglia, which signals through DAP12 to trigger phagocytosis. TREM2 SNPs have been identified as significantly increasing risk of AD in GWAS studies. The hypothesis for this increased risk is that there is a loss of function, impairing the innate immune system to clear amyloid deposition efficiently. We hypothesize that targeting TREM2 to activate the receptor will modulate the neuroinflammatory response and stimulate microglia to phagocytose and clear the amyloid deposits. Alzheimer¡¦s disease is associated with tau pathology, producing neurofibrillary tangles, and often is also accompanied by cerebrovascular pathologies. Anti-AƒÒ immunotherapy has not been shown to have any benefit on tau pathology and results in significant cerebrovascular adverse events (microhemorrhages and vasogenic edemia). We predict that activating the TREM2 receptor to modulate the neuroinflammatory response to promote clearance, will demonstrate amelioration of tau pathology, and neuroprotection. Further, we predict that TREM2 engagement will not have the cerebrovascular adverse events that are associated with anti-AƒÒ immunotherapy. To activate the TREM2 receptor, we are using an antibody developed by Alector, LLC, Alector-002a, that recognizes TREM2 and activates the receptor. We have found that the antibody show immune modulation, clearance of amyloid deposits, and cognitive improvement in amyloid depositing mice.