Alzheimer's disease (AD) is currently estimated to affect 5 million United States citizens at a cost of $100 billion/yr, numbers that are projected to increase as the population ages. The causes of AD are still unknown. However, we may be able to infer important principles from studying a small population of patients that suffer from a genetic, familial form of AD (FAD), linked to mutations in the presenilin (PS) genes. Studies on cells obtained from these patients, as well as mouse models harboring PS mutations, have observed exaggerated intracellular Ca2+ ([Ca2+]i) signaling, which occurs prior to the onset of typical AD cognitive impairments and brain lesions. These observations have provided support for the hypothesis that sustained disturbances in Ca2+ regulation are a proximal cause of AD. Nevertheless, the mechanisms by which FAD-linked PS mutations disrupt [Ca2+]i signaling, and the contribution of Ca2+ dysregulation to the onset and progression of AD in vivo, are not well understood. The goal of this proposal is to address these questions. First I will build on the in vitro observation that mutant PS disrupts [Ca2+]i signaling by increasing the probability of Ca2+ release through the endoplasmic reticulum (ER) inositol 1,4,5-trisphosphate receptor type 1 (InsP3R1) channel. To accomplish this I will introduce the opisthotonos InsP3R1 allele, which dramatically decreases InsP3R1 protein level, into a mutant PS expressing mouse line. Ca2+ imaging in neurons in brain slices from these mice will be performed to determine if decreased InsP3R1 expression alleviates the exaggerated [Ca2+]i signaling phenotype. Using these mice, I will then determine if mutant PS associated exaggerated Ca2+ release contributes to the onset and progression of the disease. Biochemical and histological techniques will be used to quantify AD lesion development. Lastly, I will conduct electrophysiological recordings in hippocampal slices to determine if normalization of [Ca2+]i signaling can rectify synaptic deficits of the AD mouse model. Completion of the proposed research may allow for identification of new drug targets to prevent or treat FAD, and may highlight the need to investigate the contribution of Ca2+ dysregulation to the common sporadic form of the disease.
Alzheimer's disease (AD) is estimated to affect five million United States citizens, with an estimated nationwide cost of $100 billion/yr, numbers that are projected to increase as the population ages. Researchers have yet to identify the initiating events in AD, and therefore current therapeutics only target the memory and cognitive symptoms associated with the disease. My proposed studies will help to identify and understand the early events leading to Alzheimer's disease, so that the next generation of disease modifying therapeutics can be designed.
|Shilling, Dustin; Müller, Marioly; Takano, Hajime et al. (2014) Suppression of InsP3 receptor-mediated Ca2+ signaling alleviates mutant presenilin-linked familial Alzheimer's disease pathogenesis. J Neurosci 34:6910-23|