Polarity dysregulation in Alzheimer’s disease

Project Summary The vast majority of Alzheimer’s disease (AD) is sporadic, with aging being the biggest risk factor. Yet age- related changes within neurons that can facilitate AD pathogenesis remain elusive. Intriguingly, there is an intricate link between aging and cell polarity. Dysregulation of polarity is observed in many cellular contexts during aging, such as increased permeability of epithelial barriers, defective asymmetric division of stem cells and increased frequency of cancer. Similarly, dysregulation of cellular polarity and compartmentalization are observed in AD neurons, with redistribution of axonal tau to the somatodendritic compartment and progressive loss of synaptic contacts. However, the mechanisms underlying this polarity dysregulation remains unclear. Remarkably, several recent genetic studies have identified PARD3, encoding the polarity protein partitioning defective 3 (Par3), as a potential novel risk gene for AD and related tauopathies. In addition, our recent work revealed Par3 shows significantly reduced expression by middle-age, and a further loss of Par3 is observed in human AD brains. Loss of Par3 increases compartmentalized APP/BACE1 convergence of amyloid precursor protein (APP) with its β-secretase BACE1, leading to intracellular β-amyloid (Aβ) accumulation. Moreover, we found forebrain conditional knockout (cKO) of Par3 leads to age-dependent tau pathology and cognitive decline, and loss of Par3 results in autophagosome accumulation, all prominent features of AD brains. Finally, phosphoproteomic profiling in Par3 cKO hippocampus reveals changes in microtubule binding proteins that are important for neuronal polarity. These exciting data have led to our central hypothesis that polarity dysregulation in aging brains leads to microtubule-based membrane transport defects that contribute to cognitive impairments in AD. Specifically, we hypothesize that loss of Par3 disrupts compartmentalized microtubule dynamics, leading to defects in polarized endolysosomal trafficking and autophagic flux in AD neurons. Aim 1 will test the hypothesis that loss of Par3 in AD disrupts polarized endolysosomal trafficking through differential regulation of dendritic and axonal microtubules. Aim 2 will test the hypothesis that loss of Par3 causes defects in autophagy and restoration of Par3 ameliorates AD pathologies. Our studies will utilize advanced molecular imaging techniques, including tauSTED super- resolution imaging, FRET, FRAP, and optogenetic manipulations of cellular and molecular activities. We combine different molecular imaging approaches with biochemical and phosphoproteomic analyses, as well as behavioral analysis in novel Par3 conditional knockout and Par3 conditional knockin mouse models. Taken together, our proposed studies will establish the molecular mechanisms by which loss of Par3 in the aging brain contributes to cognitive deficits in AD progression and whether restoring Par3 expression can ameliorate AD pathologies. The results will shed light on the mechanism of sporadic AD in which aging is the major risk factor and polarity dysregulation may be a common feature.