Alzheimer’s disease (AD) is the most common neurodegenerative disorder, affecting over 6 million Americans, with projections nearing 13 million by 2050. A defining pathological hallmark of AD is the accumulation of amyloid-beta (Aβ) plaques, which are associated with profound synaptic and neuronal loss that ultimately leads to cognitive decline. Microglia, the brain’s resident immune cells, are known to cluster around these plaques, forming a distinct plaque-associated microglial (PAM) population with a specialized transcriptional profile. Genetic studies have further implicated microglial dysfunction in AD, identifying numerous AD risk genes specifically expressed in myeloid cells. Our lab and others have shown that microglia contribute critically to Aβ plaque formation and compaction, as well as to the modulation of surrounding extracellular matrix (ECM) structures called perineuronal nets (PNNs). Pharmacological depletion of microglia using colony stimulating factor 1 receptor (CSF1R) inhibitors not only prevents plaque formation in 5xFAD mice, but also leads to an accumulation of PNNs, specialized ECM structures that enwrap cortical inhibitory neurons and regulate synaptic plasticity and memory. Importantly, PNN deficits exist in many neurological and neuropsychiatric disorders, including Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP), multiple sclerosis, traumatic brain injury, epilepsy, schizophrenia, Huntington's disease, and AD. In human AD brain tissue and the 5xFAD AD mouse model, intracellular PNN material colocalizes with PAMs, consistent with their putative phagocytic clearance. PNN loss correlates with plaque load and is prevented by microglial depletion, suggesting that microglia may actively degrade PNNs in disease. However, the functional consequences of PNN loss—and whether PNNs influence plaque formation or microglial behavior—remain unknown. Together this suggests a novel homeostatic role for microglia in PNN remodeling, with broader implications for understanding ECM dysfunction in AD. My thesis investigates how microglia regulate PNNs across both physiological and pathological states. In Chapter 1, I examine whether microglial depletion alters diurnal gene expression or PNN dynamics. In Chapter 2, I determine how loss of aggrecan, the core structural component of PNNs, impacts plaque deposition and the microglial response in the 5xFAD model. Together, these studies provide insight into the interplay between microglia, ECM integrity, and AD pathogenesis.
