Project Summary Alzheimer’s Disease (AD) is the most common cause of dementia in elderly populations. The development of effective treatments for this progressive neurodegenerative disorder has been hindered by our lack of understanding of the disease. AD is classically characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and brain-wide neuroinflammation which ultimately result in synaptic loss, neuronal dysfunction, and cognitive impairments. With our incomplete knowledge of the mechanisms underlying the emergence of these pathological hallmarks, we must focus on understanding the different aspects of disease pathology to successfully create therapies treating AD. Genome wide association studies (GWAS) have implicated microglia, the tissue-resident macrophages of the brain, as mediators of disease pathogenesis. Microglia actively maintain tissue homeostasis in the healthy brain including the regulation of lattice-like extracellular matrix (ECM) structures called perineuronal nets (PNNs). PNNs enwrap the soma and proximal synapses of different neuronal subsets and aid in learning/memory consolidation. While PNNs are naturally lost with age in wild-type (WT) mice, this loss is exacerbated in AD. Interestingly, when microglia are eliminated in the AD transgenic 5xFAD mouse model, 1) plaques fail to form and 2) PNN loss is prevented, altogether suggesting PNNs play a protective role. However, the consequences of PNN loss in AD remain unknown. To that end, we have developed two approaches to ablate PNN structures both before and after the onset of plaque deposition in order to determine their role in plaque formation, synaptic loss, and neuronal loss. In this proposal, I will determine the impact of PNNs in AD pathology by pursuing two important questions: 1) does the loss of these ECM structures facilitate plaque formation and 2) does PNN loss make neurons more susceptible to damage? Collectively, this proposal will elucidate the role of PNNs in AD – before and after the onset of plaque pathology – by exploring how their experimental ablation will affect plaque deposition, synaptic loss, and neuronal loss. Establishing whether PNNs can prevent plaque deposition as well as determining whether PNN loss in AD renders neurons more susceptible to damage is highly relevant and could lead to new therapeutic avenues that target genes/ proteins involved in PNN synthesis and degradation.