Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) play a crucial role in neuronal plasticity and survival. Increasing evidence suggests that deficient BDNF-TrkB signaling may mediate amyloid- (?)-induced neurotoxicity, synaptic dysfunction and memory deficits in Alzheimer's disease (AD). However, it has not been examined whether BDNF-TrkB dysfunction may also contribute to pathogenic mechanisms upstream to A? accumulation. Interestingly, our recent study demonstrated that the selective TrkB agonist 7,8-dihydroxyflavone not only restores impaired memory and TrkB signaling but also lowers A? levels by reducing the ?-secretase enzyme BACE1 in a mouse model of AD. In this R03 application, we will test our focused hypothesis that reduction in TrkB signaling, which is found in early AD or its harbinger mild cognitive impairment (MCI), may be responsible for inducing BACE1 elevation and consequently initiating and/or accelerating disease processes. Specifically, we will use (i) pharmacological (ANA-12, a selective and blood-brain barrier permeable TrkB antagonist) and (ii) genetic (TrkB haploinsufficiency) approaches to experimentally reproduce the impairment of TrkB signaling associated with MCI or incipient AD.
In Aim 1 -1, these approaches will be applied to young 5XFAD transgenic mice, which develop little or only faint amyloid pathology and are still normal in memory function. We will first compare the levels of BACE1 expression in ANA-12-treated 5XFAD or TrkB+/-.5XFAD bigenic mice (3-month old) with those of age-matched 5XFAD control mice. We will then explore the molecular mechanisms by which pharmacological and genetic reduction of TrkB signaling may cause BACE1 elevation (e.g., changes in transcription, translation, protein stability) and exacerbate AD-like phenotypes including memory deficits in these 5XFAD mice.
In Aim 1 -2, we will further test whether administration of ANA-12 or TrkB haploinsufficiency may be sufficient to upregulate BACE1 in wild-type mice. Given that A?42 may be important for increasing BACE1 expression in neurons around amyloid plaques during the progression of AD, it will be critical to determine a causal relationship between reduced TrkB signaling and BACE1 elevation in wild- type controls that completely lack toxic human A? species. If the data is positive, we will examine whether the same mechanisms as found in 5XFAD mice may mediate BACE1 elevation following impaired TrkB signaling in wild-type mice, regardless of the presence of human A?. Together, the proposed research is expected to address a key question whether deficient BDNF-TrkB signaling may not only be a mediator of memory impairments as a consequence of A? accumulation (as shown by previous studies) but also have a crucial role in initiating or accelerating the AD process via BACE1 elevation.
No treatment is currently available to slow or halt the deterioration of brain cells in Alzheimer's disease (AD), the most common form of dementia in the elderly. In this proposal, we will study the mechanisms by which reduced neurotrophin signaling via TrkB receptors may contribute to the excessive generation of amyloid-, a culprit to cause memory deficits in AD. Our research is expected to help to understand key molecular events that may initiate or accelerate AD processes, and could lead to new possibilities for disease-modifying therapeutic interventions.
|Ohno, Masuo (2016) Alzheimer's therapy targeting the ?-secretase enzyme BACE1: Benefits and potential limitations from the perspective of animal model studies. Brain Res Bull 126:183-198|
|Devi, Latha; Tang, Jordan; Ohno, Masuo (2015) Beneficial effects of the ?-secretase inhibitor GRL-8234 in 5XFAD Alzheimer's transgenic mice lessen during disease progression. Curr Alzheimer Res 12:13-21|
|Devi, L; Ohno, M (2015) TrkB reduction exacerbates Alzheimer's disease-like signaling aberrations and memory deficits without affecting ?-amyloidosis in 5XFAD mice. Transl Psychiatry 5:e562|
|Devi, L; Ohno, M (2015) Effects of BACE1 haploinsufficiency on APP processing and A? concentrations in male and female 5XFAD Alzheimer mice at different disease stages. Neuroscience 307:128-37|
|Devi, Latha; Ohno, Masuo (2015) A combination Alzheimer's therapy targeting BACE1 and neprilysin in 5XFAD transgenic mice. Mol Brain 8:19|
|Devi, Latha; Ohno, Masuo (2014) PERK mediates eIF2? phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer's disease. Neurobiol Aging 35:2272-81|