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Changing key signature in notion 62/29/2024 Thus, interpreting microglial modulation of AD pathophysiology requires a holistic assessment of pathological consequences at multiple levels rather than isolated readouts. ![]() Similarly, genetic methods of targeted microglial depletion have been reported to increase the size of Aβ deposits, strengthening the suggestion of a protective microglial function in limiting or compacting Aβ aggregates. However, the amelioration of amyloid pathology was associated with reduced compaction of AD-associated amyloid-β (Aβ) deposits, resulting in increased diffuse plaques and dystrophic neurites. Initial studies of microglial biology using mouse models of amyloid pathology reported reductions in amyloid burden and preservation of synapse-associated extracellular matrix (perineuronal net) following microglial depletion. Within the past two decades, genome-wide association study (GWAS) findings have identified key genetic risk variants for late-onset AD (LOAD) that are expressed exclusively or highly in microglia. However, research into Alzheimer’s disease (AD) pathogenesis focussed primarily on neurons for over 100 years after this observation. Notably, in his initial description of the pathology that adopted his name, Alois Alzheimer described aberrant glial phenotypes. In a series of publications in 1919, Pío del Río-Hortega identified that these cells are a microglial phenotype, which transition during injury, describing morphological changes and key functions and hypothesising their mesodermal origin (see ). ![]() The first descriptions of microgliosis (termed ‘rod cells’ or ‘granule cells’) were made in the 19 th and early 20 th Centuries by Rudolf Virchow, Franz Nissl, and Alois Alzheimer (amongst others see ). Some recent advances have brought modelling tools closer to human genetics, increasing the validity of both aetiological and translational endeavours. Despite the shortcomings, widely used amyloidosis and tauopathy models of the disease have proven invaluable in dissecting microglial functional responses to AD pathophysiology. Insufficiencies of mouse genetics and aggressive transgenic modelling imply severe limitations in applying current methodologies for aetiological investigations. We note that impairment to protective phenotypes may include prolonged or insufficient microglial activation, resulting in dysregulated metabolomic (notably lipid-related) processes, compounded by age-related inflexibility in dynamic responses. Herein, we review some key findings from clinical and animal model investigations, discussing the role of microglial genetics in mediating perturbations from homeostasis. ![]() Despite expressing many key risk genes, the role of microglia in late-onset Alzheimer’s disease pathophysiology is somewhat ambiguous, with various phenotypes reported to be either harmful or protective.
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