Alzheimer's disease (AD) is an age dependent neurodegenerative disorder and the most common form of dementia affecting the elderly. The neuropathological hallmarks of AD include extracellular ss-amyloid- containing plaques and intracellular neurofibrillary tangles composed of phosphorylated tau protein in the hippocampus and neocortex, and degeneration and loss of basal forebrain cholinergic neurons (BFCN). BFCN project to the hippocampus and cerebral cortex where the release of their neurotransmitter, acetylcholine (ACh), is central to cognition. A decline in BFCN function and cholinergic marker is apparent in AD patients and in animal models of AD. Thus, it has been postulated that the dysfunction and/or degeneration of BFCN contributes to the memory deficits associated with AD. Many of the available treatments for AD are designed to inhibit the breakdown of ACh, though the administration of trophic factors that support the function and survival of cholinergic neurons has also been explored. One such neurotrophin is brain derived neurotrophic factor (BDNF) that signals via the TrkB receptor. The reduced expression of mRNAs encoding TrkB in purified BFCN from AD patients, suggests that BDNF therapy could prevent or restore the functional impairments of these neurons in AD. This approach has been hampered by to the poor pharmacokinetics of BDNF that does not cross the blood-brain barrier. Recently a potent and selective TrkB agonist that readily enters the brain when administered peripherally was discovered 7,8-dihydroxyflavone (7,8-DHF). Beneficial effects of 7,8-DHF have been reported in models of Parkinson's disease, AD and post-traumatic stress disorder and we are presenting preliminary data of DHF treatment in mouse models of AD and amyotrophic lateral sclerosis that strongly support these reports. We hypothesize that 7,8-DHF, a TrkB agonist, will delay or lessen memory loss and reduce amyloid pathology through its neurotrophic effects on hippocampal and basal forebrain cholinergic neurons. To test our hypothesis APP.PS1/CHGFP mice will be treated with 7,8-DHF from 1 to 6 months (early pathology) or 12 months (late pathology). We will measure the effects of 7,8-DHF treatment on animals' memory and learning using Morris water maze test, BFCN gene expression pattern by microarray and RT-PCR of FACS purified BFCN, hippocampal ACh content and release by high-performance liquid chromatography (HPLC), amyloid pathology by immunohistochemistry (IHC) and ELISA and indices of hippocampal and cerebral cortical function assessed by IHC techniques including cholinergic neurons and cholinergic fibers, neurogenesis and synapses and dendritic spines. We will also measure neurochemical profile using magnetic resonance spectroscopy (MRS). Our proposed studies incorporate principals of rational pharmacology with state-of-the-art neuropathological, neurochemical, gene-analysis and MR techniques with cognitive evaluation to comprehensively assess the brain of a unique Alzheimer mouse model that expresses green fluorescent protein specifically in cholinergic cells. These studies will help further define the therapeutic benefits of a novel neurotrophic compound that crosses the blood-brain barrier but also will provide an entirely new level of understanding of the basic biology of BFCN and their function in AD and characterize a novel model for future use to test therapeutics relevant to patients with AD.
AD is a devastating, incurable disease that robs elderly Veterans of their mental abilities and creates an enormous burden on families, caregivers and the entire VA health care system. As our Veteran population ages, these individuals and family members become increasingly susceptible to age-related diseases such as AD. By the year 2025, at least 11 million people are expected to suffer from AD. Our proposed studies incorporate principals of rational pharmacology with state-of- the-art neuropathological, neurochemical and gene-analysis techniques with cognitive evaluation to comprehensively assess the brain of a unique Alzheimer mouse model that expresses green fluorescent protein specifically in cholinergic cells. These studies will help further define the therapeutic benefits of a novel neurotrophic compound that crosses the blood-brain barrier but also provide an entirely new level of understanding of the basic biology of BFCN and their function in AD and characterize a novel model for future use to test therapeutics relevant to patients with AD.
|Aytan, Nurgul; Choi, Ji-Kyung; Carreras, Isabel et al. (2018) Protective effects of 7,8-dihydroxyflavone on neuropathological and neurochemical changes in a mouse model of Alzheimer's disease. Eur J Pharmacol 828:9-17|