Immunoneurology; targeting the brain Immune system as a novel therapeutic strategy for dementia and neurodegeneration

Abstract

Abstract Immuno‐neurology: targeting the brain Immune system as a novel therapeutic strategy for dementia and neurodegenerationFor the last two decades, the predominant approach to treating neurodegenerative disorders was to remove or disaggregate disease‐typifying, misfolded proteins or prevent their synthesis. Multiple clinical trials with drugs that counteract beta‐amyloid or Tau protein in Alzheimer’s disease (AD), Alpha‐Synuclein in Parkinson’s disease, SOD1, C9orf72, and TDP‐43 in ALS, and the Htt protein in Huntington’s disease, are still in progress. An alternative broad‐based therapeutic strategy for degenerative brain disorders is to recruit the brain’s immune system to thwart multiple disease pathologies. This approach, designated immuno‐neurology, is conceptually akin to immuno‐oncology, which revolutionized cancer therapy by recruiting the immune system to counteract tumor growth. Immuno‐neurology hypothesizes that impaired activities of microglia the innate immune cells of the brain, due to normal aging or genetic mutations cause havoc in our brain’s ability to function and deal with insults and thus enable neurodegeneration. The scientific rationale for immuno‐neurology is derived from our growing understanding of the role human genetics and microglia play in the etiology of brain disorders. Human genetics revealed that while AD is characterized by synaptic and neuronal loss, many genetic variations that increase the risk to develop AD reside in genes that are specifically expressed in, and control the survival and function of, microglia. Microglia are now known to be key regulators of brain well‐being. They are responsible for the removal of misfolded proteins, myelin debris, and disease‐causing agents as well as the repair of leaky blood vessels and injured brain tissue. In addition, microglia, directly and indirectly, regulate brain function by controlling the number of synaptic connections and the survival or activity of oligodendrocytes, astrocytes, and endothelial cells. Using familial risk genes that regulate microglia, such as Progranulin, TREM2, CD33, and MS4A, as levers to repair and harness these critical brain immune cells has emerged as a promising therapeutic strategy for degenerative brain disorders.