Alzheimer's disease (AD) is the most common cause of cognitive impairment in older patients and is expected to increase greatly in prevalence. Neuropathologically, AD is characterized by beta-amyloid containing plaques, tau-containing neurofibrillary tangles, and neuronal loss. A well described yet underappreciated eariy feature of AD pathogenesis is the degeneration ofthe locus coeruleus (LC), which is the sole source of forebrain norepinephrine (NE). Previous studies have shown that LC lesions exacerbate AD-like neuropathology and cognitive deficits in mouse models of AD, while increasing NE is neuroprotective. However, the mechanism underiying the protective effect of LC neurons in AD is not understood. We have recently discovered that NE and other endogenous catecholamines function as direct agonists forthe TrkB neurotrophin receptor. TrkB signaling is neuroprotective, retards A(3 toxicity, and is critical for neuronal plasticity and learning and memory. The goal of this proposal is to test whether this novel NE-TrkB interaction contributes to the role ofthe LC in AD pathogenesis.
In Aim 1, we will test the ability of NE and novel synthetic catecholamine-derived TrkB agonists to decrease AB production and toxicity in primary neuronal cultures.
In Aim 2, we will test the ability of the most promising TrkB agonists identified in Aim 1 to ameliorate AD-like neuropathology and cognitive deficits in a transgenic mouse model of AD.
In Aim 3, we will test the hypothesis that LC loss in mild cognitive impairment (MCI) and AD impairs TrkB activation and correlates with amyloid pathology and cognitive impairment using human postmortem cases.
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