Basic Science and Pathogenesis.

Background: Condensed extracellular matrix structures called perineuronal nets (PNNs) preferentially enwrap the soma and stabilize proximal synapses of parvalbumin-expressing inhibitory neurons in the cortex, serving as a protective barrier against neurotoxins. While PNN structural integrity declines in the healthy aging brain, this reduction is exacerbated in Alzheimer's disease (AD). In the 5xFAD mouse model of amyloidosis, the elimination of microglia prevents reductions in PNN, suggesting microglia are responsible for the over-degradation of PNNs observed in AD.

Cortical diurnal rhythms remain intact with microglial depletion.

Microglia are subject to change in tandem with the endogenously generated biological oscillations known as our circadian rhythm. Studies have shown microglia harbor an intrinsic molecular clock which regulates diurnal changes in morphology and influences inflammatory responses. In the adult brain, microglia play an important role in the regulation of condensed extracellular matrix structures called perineuronal nets (PNNs), and it has been suggested that PNNs are also regulated in a circadian and diurnal manner.

Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain.

Background: Microglia, the brain's principal immune cell, are increasingly implicated in Alzheimer's disease (AD), but the molecular interfaces through which these cells contribute to amyloid beta (Aβ)-related neurodegeneration are unclear. We recently identified microglial contributions to the homeostatic and disease-associated modulation of perineuronal nets (PNNs), extracellular matrix structures that enwrap and stabilize neuronal synapses, but whether PNNs are altered in AD remains controversial.

Methods: Extensive histological analysis was performed on male and female 5xFAD mice at 4, 8, 12, and 18 months of age to assess plaque burden, microgliosis, and PNNs.