Primary Microglia Dysfunction or Microgliopathy: A Cause of Dementias and Other Neurological or Psychiatric Disorders

Abstract

Microglia are unique cells in the central nervous system (CNS), being considered a sub-type of CNS macrophage. These cells monitor nearby micro-regions, having roles that far exceed immunological and scavengering functions, being fundamental for developing, protecting and maintaining the integrity of grey and white matter. Microglia might become dysfunctional, causing abnormal CNS functioning early or late in the life of patients, leading to neurologic or psychiatric disorders and premature death in some patients. Observations that the impairment of normal microglia function per se could lead to neurological or psychiatric diseases have been mainly obtained from genetic and molecular studies of Nasu-Hakola disease, caused by TYROBP or TREM2 mutations, and from studies of adult-onset leukoencephalopathy with axonal spheroids (ALSP), caused by CSF1R mutations. These classical microgliopathies are being named here Microgliopathy Type I. Recently, mutations in TREM2 have also been associated with Alzheimer Disease. However, in Alzheimer Disease TREM2 allele variants lead to an impaired, but functional TREM2 protein, so that patients do not develop Nasu-Hakola disease but are at increased risk to develop other neurodegenerative diseases. Alzheimer Disease is the prototype of the neurodegenerative disorders associated with these TREM2 variants, named here the Microgliopathies Type II. Here, we review clinical, pathological and some molecular aspects of human diseases associated with primary microglia dysfunctions and briefly comment some possible therapeutic approaches to theses microgliopathies. We hope that our review might update the interesting discussion about the impact of intrinsic microglia dysfunctions in the genesis of some pathologic processes of the CNS.

Keywords: leukoencephalopathies; microglia; microgliopathies; neurodegenerative diseases; white matter diseases.