Maguire-Zeiss, K. A. | Search bioRxiv

bioRxiv2025

Age-related inflammatory changes and perineuronal net dynamics: implications for neurodegenerative disorders.

BackgroundHealthy aging alone can lead to cognitive decline, decreased brain size, protein aggregation, accumulation of senescent cells and neuroinflammation. Furthermore, age is the primary risk factor for several neurodegenerative disorders such as Parkinsons and Alzheimers disease. Age-related neuroinflammation, as known as inflammaging, is thought to restrict brain plasticity. Perineuronal nets (PNNs), specialized extracellular matrix structures surrounding fast-spiking parvalbumin (PV) interneurons, regulate plasticity and protect neurons from oxidative stress. Given the known impact of inflammaging on neural circuits, this study examines age-associated changes in PNN homeostasis, glial activation, and neuroinflammation in two brain regions relevant to age-related neurodegenerative diseases. MethodsWe analyzed young (4-month-old) and aged (22-month-old) C57BL/6J male mice for several behavioral phenotypes [hippocampal-dependent spatial learning using the Barnes maze; locomotion and anxiety-related behaviors using Open field and T-maze]. Using immunostaining, PNNs (Wisteria floribunda agglutinin and aggrecan), PV interneurons, and microglial activation (Iba1) were quantified in both the hippocampus and dorsal striatum. Glial morphology was examined using a battery of cell body, branching, and endpoint analyses. Quantitative RT-PCR was used to analyze changes in the gene expression of inflammatory and extracellular matrix markers. ResultsAged mice exhibited hippocampal-dependent memory deficits without alterations in locomotion or anxiety-related behavior. PNN counts increased in the aged hippocampus, particularly in CA2, with a higher proportion of WFA+ and aggrecan+ PNNs. In contrast, PNN homeostasis was maintained in the dorsal striatum. In general, Aged mice showed increases in microglial activation and a subset of inflammatory markers. We report brain region- and age-specific gene expression changes in complement, matrix metalloproteinases, and other inflammatory markers. Aged striatal microglia displayed an activated morphology with larger cell bodies and reduced branching, as well as increased expression of markers for microgliosis (Iba1, TREM2, CD68). ConclusionsThese findings suggest that aging differentially affects neuroinflammation and PNN integrity across brain regions. The hippocampus exhibits PNN accumulation, neuroinflammation, and behavioral changes, whereas the striatum maintains PNN homeostasis concurrent with increased microglial activation. This work suggests that neuroinflammation contributes to age-related changes in PNNs and behavior underscoring the importance of region-specific therapeutic strategies targeting PNN regulation.

neuroscience↗

bioRxiv2023

Jedi-1/MEGF12-mediated phagocytosis controls the pro-neurogenic properties of microglia in the ventricular-subventricular zone

Microglia are the primary phagocytes in the central nervous system and are responsible for clearing dead cells generated during development or disease. The phagocytic process shapes the phenotype of the microglia, which affects the local environment. A unique population of microglia reside in the ventricular-subventricular zone (V-SVZ) of neonatal mice, but how they influence this neurogenic niche is not well-understood. Here, we demonstrate that phagocytosis creates a pro-neurogenic microglial phenotype in the V-SVZ and that these microglia phagocytose apoptotic cells via the engulfment receptor Jedi-1. Deletion of Jedi-1 decreases apoptotic cell clearance, triggering the development of a neuroinflammatory phenotype, reminiscent of neurodegenerative and-age-associated microglia, that reduces neural precursor proliferation via elevated interleukin (IL)-1{beta} signaling; inhibition of IL-1 receptor rescues precursor proliferation in vivo. Together, these results reveal a critical role for Jedi-1 in connecting microglial phagocytic activity to a phenotype that promotes neurogenesis in the developing V-SVZ. Graphical Abstract. Jedi-1-dependent phagocytosis supports neurogenesis via suppression of microglial inflammatory pathway activationTop: Wild-type Proliferative-zone-Associated Microglia (PAMs) (cyan) use the engulfment receptor Jedi-1 ( Jedi) to engulf apoptotic cells (yellow) in the neurogenic ventricular-subventricular zone (V-SVZ) of the early postnatal brain. Jedi activation supports neural precursor cell (NPC) proliferation and the generation of new neurons. Bottom: Deletion of Jedi reduces microglial phagocytosis and transforms PAMs into Disease-associated Inflammatory Microglia (DIMs) characterized by the upregulation of canonical inflammatory genes and core DIM markers iden ified in the aging and neurodegenerative brain (Nlrp3, NLR family pyrin domain-containing 3; Tnf, tumor necrosis factor; Ccl4, C-C chemokine ligand 4 (also called macrophage inflammatory protein 1{beta}); Ccr5, C-C chemokine receptor type 5). Increased interleukin-1{beta} (IL-1{beta}) synthesis, release, and signaling in the Jedi-null V-SVZ reduces NPC proliferation and newborn neuron number. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/531012v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@16b9785org.highwire.dtl.DTLVardef@a8be50org.highwire.dtl.DTLVardef@66b726org.highwire.dtl.DTLVardef@1825d8b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThe engulfment receptor Jedi-1 is expressed by microglia in the neonatal ventricular-subventricular zone (V-SVZ) neurogenic niche. C_LIO_LIJedi-1 knockout microglia have decreased engulfment ability, resulting in accumulation of dead cells in the V-SVZ. C_LIO_LILoss of Jedi-1 leads to a neuroinflammatory phenotype in microglia that is characteristic of neurodegenerative and age-associated microglia. C_LIO_LIMicroglial-specific loss of Jedi-1 reduces neurogenesis, which is rescued in vivo by inhibition of interleukin-1{beta} signaling. C_LI

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