Dysfunctional homeostatic plasticity in Alzheimer's Disease

Tulane University Of Louisiana, New Orleans LA

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Abstract

PROJECT SUMMARY/ABSTRACT Brain performance declines with Alzheimer?s disease (AD) progression. The massive loss of neurons observed at advances stages of the disease are confirmatory observations of the disruption of the brain circuits governing the brain tasks affected. This is, however, too late in the progression of the disease. Beta-amyloid (A?) progressively accumulates over many years, surpassing its physiological levels early in the disease. Unfortunately, little is known about the effects of A? before the first symptoms appear. By then, it has been reported, among other things, that there is an increase in the excitability of the neurons. We found that cortical pyramidal neurons of young APPNL-G-F mice, a relatively novel mouse model of AD that does not overexpress amyloid precursor protein, but accumulates A? aggressively after the second month of life, present with physiological features that indicate a reduction of their intrinsic excitability when compared with neurons from age-matched controls. The same indicators 3-4 months later, when the accumulation of A? is significant, show a swing in their excitability, and the neurons become more excitable than in control mice, results more in agreement with the data from the literature. We believe that sustained hypoexcitability results in impaired homeostatic mechanisms of intrinsic excitability in 6-month-old mice. Our hypothesis is that early accumulation of A? leads to hypoexcitability of cortical neurons resulting in a pathological hyperexcitability at later stages of the disease. This abnormal switch in excitability is a consequence of an impairment of the homeostatic mechanism caused by upregulation of CaMKIV activity. The questions that arise now are how early A? accumulation leads to hypoexcitability, what causes the rebound in excitability a few months later, and whether there is a manipulation that could correct the hypoexcitable state to prevent the hyperexcitable state. To answer these questions we will test the following hypotheses: (1) hypoexcitability in the young APPNL-G-F mice is caused by upregulation of voltage-gated potassium channels, downregulation of voltage-gated sodium channels changes, or both, (2) defective or saturated mechanisms of homeostatic plasticity lead to hypoexcitability at younger ages, (3) homeostatic plasticity dysregulation is a direct consequence of A? accumulation, (4) hypoexcitability occurring during young adulthood in the progression of pathology in the APPNL-G-F mouse model is a cause of hyperexcitability at later stages (middle age), (5) early hypoexcitability results in blunted homeostatic response at middle age, due to downregulation of CaMKIV, and (6) long-term block of K+ channels using FDA- approved drugs during early stages of the pathology will increase homeostatic downregulation of excitability. We will use APP knock-in (APPNL-G-F) transgenic mice, the most clinically relevant mouse model of AD, in vivo 2PE microscopy, optogenetics, chemogenetics, and electrophysiological recordings to test our hypotheses. Aim 1 will identify the mechanisms responsible for early, pre-plaque hypoexcitability of pyramidal neurons in APPNL-G-F mice and Aim 2 will determine if interventions aimed to correct early hypoexcitability of pyramidal neurons can prevent or decrease middle age hyperexcitability. By using state of the art techniques and innovative experimental and animal models, we will elucidate the effects of the progression of the AD pathology on neuronal homeostatic mechanisms. This study has the potential to generate novel knowledge on the deficits impacting brain function before the appearance of cognitive symptoms for the design and improvement of personalized or precision interventions aimed to prevent or delay cognitive disturbances in Alzheimer?s disease patients.