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.
|Ebbert, Mark T W; Boehme, Kevin L; Wadsworth, Mark E et al. (2016) Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk. Alzheimers Dement 12:121-9|
|Zhang, Yuhai; Zhou, Xiao-Hua; Meranus, Dana H et al. (2016) Benzodiazepine Use and Cognitive Decline in Elderly With Normal Cognition. Alzheimer Dis Assoc Disord 30:113-7|
|LeVine 3rd, Harry; Walker, Lary C (2016) What amyloid ligands can tell us about molecular polymorphism and disease. Neurobiol Aging 42:205-12|
|Holler, Christopher J; Taylor, Georgia; McEachin, Zachary T et al. (2016) Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia. Mol Neurodegener 11:46|
|Buijsen, R A M; Visser, J A; Kramer, P et al. (2016) Presence of inclusions positive for polyglycine containing protein, FMRpolyG, indicates that repeat-associated non-AUG translation plays a role in fragile X-associated primary ovarian insufficiency. Hum Reprod 31:158-68|
|Forrester, Sarah N; Gallo, Joseph J; Smith, Gwenn S et al. (2016) Patterns of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Risk of Dementia. Am J Geriatr Psychiatry 24:117-25|
|White, Matthew T; Shaw, Leslie M; Xie, Sharon X et al. (2016) Evaluation of Cerebrospinal Fluid Assay Variability in Alzheimer's Disease. J Alzheimers Dis 51:463-70|
|Rui, Yanfang; Zheng, James Q (2016) Amyloid Î² oligomers elicit mitochondrial transport defects and fragmentation in a time-dependent and pathway-specific manner. Mol Brain 9:79|
|Hampstead, B M; Khoshnoodi, M; Yan, W et al. (2016) Patterns of effective connectivity during memory encoding and retrieval differ between patients with mild cognitive impairment and healthy older adults. Neuroimage 124:997-1008|
|Seyfried, Nicholas T; Dammer, Eric B; Swarup, Vivek et al. (2016) A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer's Disease. Cell Syst :|
Showing the most recent 10 out of 293 publications