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

Abstract

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. Findings were validated in postmortem AD tissue. The role of neuroinflammation in PNN loss was investigated via LPS treatment, and the ability to prevent or rescue disease-related reductions in PNNs was assessed by treating 5xFAD and 3xTg-AD model mice with colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia. Findings Utilizing the 5xFAD mouse model and human cortical tissue, we report that PNNs are extensively lost in AD in proportion to plaque burden. Activated microglia closely associate with and engulf damaged nets in the 5xFAD brain, and inclusions of PNN material are evident in mouse and human microglia, while aggrecan, a critical PNN component, deposits within human dense-core plaques. Disease-associated reductions in parvalbumin (PV)+ interneurons, frequently coated by PNNs, are preceded by PNN coverage and integrity impairments, and similar phenotypes are elicited in wild-type mice following microglial activation with LPS. Chronic pharmacological depletion of microglia prevents 5xFAD PNN loss, with similar results observed following depletion in aged 3xTg-AD mice, and this occurs despite plaque persistence. Interpretation We conclude that phenotypically altered microglia facilitate plaque-dependent PNN loss in the AD brain. Funding The NIH (NIA, NINDS) and the Alzheimer's Association.

Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

“…Recent studies have identified a novel contribution of microglia in modulating perineuronal nets (PNNs) in the adult brain 60, 61 , specialized extracellular matrix assemblies that enwrap neurons and proximal dendrites to regulate synaptic plasticity 62 , protect against neurotoxins 63 , and enhance signal propagation 60, 61 , among other functions. In control brains, PNNs (as detected by Wisteria floribunda agglutinin (WFA) staining) are preferentially found on parvalbumin (PV) expressing cells.…”

A two-hit adversity model in developing rats reveals sex-specific impacts on prefrontal cortex structure and behavior

“…Recent work has elucidated potential mechanisms by which PNNs are degraded in response to altered experience and neuropsychiatric conditions. For example, microglia have been implicated in PNN structural development and degradation ( Crapser et al, 2020a , b ; Nguyen et al, 2020 ). Further, sex differences have been observed in the neuroimmune response to stress ( Fonken et al, 2018 ; Gildawie et al, 2020b ), suggesting a microglia-mediated mechanism may underlie differences between males and females in their behavioral and neural response to repeated adversity during sensitive periods of development.…”

An Extracellular Perspective on CNS Maturation: Perineuronal Nets and the Control of Plasticity

“…Two hallmarks of AD are extraneuronal deposition of the amyloid-beta protein in the form of plaques and intraneuronal aggregation of the microtubule-associated protein tau in the form of filaments [ 227 , 228 ]. Some studies document a partial loss of CS-GAGs/CSPGs in the PNNs of patients and mouse models of AD, particularly in the cingulate, frontal, temporal, and entorhinal cortexes [ 224 , 229 , 230 ] and middle frontal gyrus [ 231 ] in humans, and in the hippocampus CA1, CA2, and CA3 [ 232 ], subiculum, and visual cortex [ 231 ] in mice. However, other studies report no alteration of PNNs in the brains of AD patients or mice in the human insular cortex and subcortical regions [ 233 ]; human primary sensory, secondary, and associative areas of the temporal and occipital lobe [ 234 ]; mouse parietal cortex [ 233 ].…”

“…However, other studies report no alteration of PNNs in the brains of AD patients or mice in the human insular cortex and subcortical regions [ 233 ]; human primary sensory, secondary, and associative areas of the temporal and occipital lobe [ 234 ]; mouse parietal cortex [ 233 ]. A recent study pointed to an intriguing role of microglia activation, triggered by amyloid plaques, in mediating extensive PNN loss in a mouse model of AD [ 231 ]. While there are no studies reporting a PNN increase in human AD brains, mice characterized by amyloid-beta plaque production (APP/PS1 mice) show increased WFA labeling around hippocampal PV neurons and the upregulation of several ECM proteins in hippocampal synaptosome preparations at early stages (3 months of age), when amyloid-beta plaques are not yet observed, but when contextual fear memory is impaired and long-term potentiation (LTP) is reduced.…”