title: Microglial malfunction: the third rail in the development of Alzheimer's disease.
abstract: Studies of Alzheimer's disease (AD) have predominantly focused on two major pathologies: amyloid-β (Aβ) and hyperphosphorylated tau. These misfolded proteins can accumulate asymptomatically in distinct regions over decades. However, significant Aβ accumulation can be seen in individuals who do not develop dementia, and tau pathology limited to the transentorhinal cortex, which can appear early in adulthood, is usually clinically silent. Thus, an interaction between these pathologies appears to be necessary to initiate and propel disease forward to widespread circuits. Recent multidisciplinary findings strongly suggest that the third factor required for disease progression is an aberrant microglial immune response. This response may initially be beneficial; however, a maladaptive microglial response eventually develops, fueling a feed-forward spread of tau and Aβ pathology.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Stanford Neurosciences Institute, Stanford, CA, USA.
authors.forename: Siddhita D
authors.initials: SD
authors.lastname: Mhatre
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Stanford Neurosciences Institute, Stanford, CA, USA; Neurosciences Graduate Program, Stanford University, Stanford, CA, USA.
authors.forename: Connie A
authors.initials: CA
authors.lastname: Tsai
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Stanford Neurosciences Institute, Stanford, CA, USA; Neurosciences Graduate Program, Stanford University, Stanford, CA, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Rubin
authors.affiliation: Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: James
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Stanford Neurosciences Institute, Stanford, CA, USA. Electronic address: kandreas@stanford.edu.
authors.forename: Katrin I
authors.initials: KI
authors.lastname: Andreasson
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology*; D000818:Animals; D001921:Brain / Q000276:immunology; D006801:Humans; D017628:Microglia / Q000276:immunology*
keywords: Alzheimer's disease; Aβ peptide; Braak stages; GWAS; epigenomics; microglia; tau phosphorylation; transcriptomics