UC Irvine

Alzheimer’s Disease (AD) is one of the most prevalent neurodegenerative diseases. It’s estimated that by 2060 there will be 13.8 million people aged 65 and older with AD (Alzheimer’s Association, 2025). Neurodegeneration is a primary pathological feature of late-stage Alzheimer’s Disease (AD), including dendritic atrophy, axonal destabilization and neuronal death yet mechanisms are not well understood. Early in disease onset, AD is primarily characterized by the accumulation of extracellular amyloid beta (Aß) plaques and intracellular neurofibrillary tangles in neurons. The prevailing hypothesis, “amyloid hypothesis,” driving the field has been that neuronal dysfunction and degeneration are driven by extracellular Aß in one form or another. New antibody treatments that target Aß have been approved by the FDA, but so far, these result in only mild delays in cognitive impairment, have potentially serious side effects, and may not delay neurodegeneration. Accordingly, there is a major un-met need to identify mechanisms underlying neurodegeneration and identify potential interventions to slow down its rate and progression. In chapter 2, we validate a method for labeling and tracking neurodegeneration in a mouse model of AD. In chapter 3, we test whether Adeno-associated Virus (AAV)-based interventions that activate the AKT/Mechanistic target of Rapamycin (mTOR) pathway are a potential therapeutic target for promoting neuronal survival. In chapter 4, we assess whether mTOR activation, via PTEN deletion, in corticospinal neurons (CSNs) delays motor deficits in AD.