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.
|Rangaraju, Srikant; Raza, Syed Ali; Li, Noel Xiang'An et al. (2018) Differential Phagocytic Properties of CD45low Microglia and CD45high Brain Mononuclear Phagocytes-Activation and Age-Related Effects. Front Immunol 9:405|
|Burke, Shanna L; Hu, Tianyan; Fava, Nicole M et al. (2018) Sex differences in the development of mild cognitive impairment and probable Alzheimer's disease as predicted by hippocampal volume or white matter hyperintensities. J Women Aging :1-25|
|Chalermpalanupap, Termpanit; Schroeder, Jason P; Rorabaugh, Jacki M et al. (2018) Locus Coeruleus Ablation Exacerbates Cognitive Deficits, Neuropathology, and Lethality in P301S Tau Transgenic Mice. J Neurosci 38:74-92|
|Maezawa, Izumi; Nguyen, Hai M; Di Lucente, Jacopo et al. (2018) Kv1.3 inhibition as a potential microglia-targeted therapy for Alzheimer's disease: preclinical proof of concept. Brain 141:596-612|
|Bishof, Isaac; Dammer, Eric B; Duong, Duc M et al. (2018) RNA-binding proteins with basic-acidic dipeptide (BAD) domains self-assemble and aggregate in Alzheimer's disease. J Biol Chem 293:11047-11066|
|Peng, Katherine Y; Pérez-González, Rocío; Alldred, Melissa J et al. (2018) Apolipoprotein E4 genotype compromises brain exosome production. Brain :|
|Gangishetti, Umesh; Christina Howell, J; Perrin, Richard J et al. (2018) Non-beta-amyloid/tau cerebrospinal fluid markers inform staging and progression in Alzheimer's disease. Alzheimers Res Ther 10:98|
|Zhang, Qi; Ma, Cheng; Gearing, Marla et al. (2018) Integrated proteomics and network analysis identifies protein hubs and network alterations in Alzheimer's disease. Acta Neuropathol Commun 6:19|
|Umoh, Mfon E; Dammer, Eric B; Dai, Jingting et al. (2018) A proteomic network approach across the ALS-FTD disease spectrum resolves clinical phenotypes and genetic vulnerability in human brain. EMBO Mol Med 10:48-62|
|Wang, Qi; Guo, Lei; Thompson, Paul M et al. (2018) The Added Value of Diffusion-Weighted MRI-Derived Structural Connectome in Evaluating Mild Cognitive Impairment: A Multi-Cohort Validation1. J Alzheimers Dis 64:149-169|
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