Tuesday, May 13, 2025
5/13/2025
A unique subpopulation of wild-type neurons recapitulating FAD phenotypes - Abstract People with late-onset sporadic Alzheimer’s disease (SAD) display overall the same clinical and pathological features as those with early-onset familial AD (FAD). However, the mechanism(s) underlying the clinicopathologic commonality between these two genetically distinct AD forms is unclear. Our overall hypothesis is that a subpopulation of wild-type neurons in the brain strikingly recapitulates the phenotypes of neurons expressing FAD mutant Presenilin (PSEN) (perhaps via post-translational modification of wild-type PSEN1), and this selective cell population plays a role in SAD neurodegeneration. Several pieces of evidence support this hypothesis. First, we showed that wild-type PSEN1 in a subset of neurons within the SAD brain displays a conformation similar to FAD mutant PSEN1 (Wahlster et al. Acta Neuropathol 2013). Second, we uncovered that PKA-mediated PSEN1 phosphorylation at Ser310 is significantly upregulated in SAD brains, and this post translational modification, together with phosphorylation of two other sites, steers wild-type PSEN1 conformation towards that of FAD mutant PSEN1 (Maesako et al. eLife 2017). Lastly, we have recently developed novel genetically encoded FRET-based biosensors that for the first time allow quantitative recording of the gamma-secretase activity over time, on a cell-by-cell basis, in live neurons (Maesako et al. iScience 2020, Houser et al. Sensors 2020, Houser et al. Biosensors 2021, Maesako et al. J Neurosci 2022). Surprisingly, these biosensors have enabled us to discover a unique subpopulation of wild-type neurons displaying diminished endogenous gamma-secretase activity. More importantly, our strong preliminary data show that this cell population recapitulates several key characteristics that have been identified in neurons expressing FAD mutant PSEN; these include impaired gamma-secretase “processivity” and thus predominant production of long Aβ, endo-lysosomal abnormalities, and vulnerability phenotypes in response to toxic insults. Therefore, this proposal will further employ multiple model systems and complementary assays to establish the molecular basis and physiological relevance that support our hypothesis. Aim 1 will elucidate the molecular mechanism(s) underlying the heterogeneity in endogenous gamma-secretase activity and its consequences in neurons. Aim 2 will further verify the cause-and-effect relationship between dysfunctional gamma-secretase, endo-lysosomal abnormalities, and neuronal vulnerability. More importantly, we will explore the therapeutic potential of the US FDA-approved compounds that could potentially function as gamma-secretase modulators (GSMs) or gamma-secretase activators (GSAs). Aim 3 will determine if the unique FAD-like neuronal population exists in “AD” mouse models endogenously expressing wild-type PSEN, as our preliminary results indicate, in iPSCs derived human neurons and post-mortem brains from SAD cases. Given that promoting neuronal resilience could be a new therapeutic strategy for AD, a better understanding of the molecular basis behind the newly discovered selectively vulnerable cell population will open a new path for developing novel therapeutic opportunities.
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