Aging Brain Builds PNN Armor in Hippocampus While Striatum Stays Inflamed

Age is the single greatest risk factor for neurodegenerative diseases like Alzheimer's and Parkinson's, yet most disease models fail to account for the effects of normal aging alone. Researchers at Georgetown University set out to characterize how healthy aging reshapes the brain's immune environment and the specialized extracellular scaffolding known as perineuronal nets (PNNs) — lattice-like structures that wrap around fast-spiking parvalbumin (PV) interneurons and are critical for regulating neural circuit plasticity and protecting neurons from oxidative stress.

The study compared young (4-month-old) and aged (22-month-old) male C57BL/6J mice across behavioral, histological, and molecular measures in the hippocampus and dorsal striatum — two regions central to memory and motor function, respectively. Aged mice showed significant hippocampal-dependent spatial memory deficits on the Barnes maze, including longer latency to locate the escape hole and reduced use of direct search strategies, without differences in locomotion or anxiety-like behavior on open field or T-maze tests, suggesting the deficits were cognitively specific rather than motor-related.

In the hippocampus, aging produced a marked increase in PNN density. Specifically, the CA2 subregion showed the greatest accumulation, with higher proportions of both WFA-positive and aggrecan-positive PNNs in aged animals. This accumulation is notable because excessive PNNs are thought to restrict synaptic plasticity — the cellular basis of learning and memory. By contrast, PNN homeostasis was largely preserved in the dorsal striatum of aged animals, indicating that PNN regulation is not a uniform brain-wide process but is regionally determined.

Microglial activation data revealed a complementary but distinct pattern. Aged striatal microglia displayed morphological hallmarks of activation: significantly larger cell bodies, reduced branching complexity on Sholl analysis, and fewer terminal process endpoints — all consistent with a transition from a ramified, surveilling state toward an activated, reactive phenotype. Gene expression analysis confirmed upregulation of microglial activation markers including Iba1, TREM2, and CD68 in aged striatum. Complement system genes and matrix metalloproteinases (MMPs) also changed in region- and age-specific patterns, with MMP dysregulation potentially contributing to altered PNN remodeling.

The authors propose that the hippocampal PNN accumulation and concurrent neuroinflammation together impair the plasticity of PV interneuron circuits, contributing to the observed memory deficits. In the striatum, maintained PNN integrity alongside elevated microglial activation may represent an early warning state — inflammation without yet-apparent structural ECM disruption — possibly relevant to prodromal stages of Parkinson's disease. A key caveat is that the study used only male mice (N=5 per group), limiting generalizability. Nonetheless, the findings underscore that inflammaging affects distinct brain regions through mechanistically different pathways, and that any therapeutic intervention targeting PNN regulation or neuroinflammation must account for regional specificity rather than applying a one-size-fits-all approach.