Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population. Most AD research has focused on understanding how beta-amyloid (Abeta) peptide accumulation, and neurofibrillary tangles (NFT), contribute to the cause of AD. There is, however, less known about how these events lead to the later manifestations of AD, such as progressive neurodegeneration and a decline in cognitive and motor function. With no current cure for AD (prevention of the primary events), understanding the subsequent cellular events that underlie disease progression may give important insight into potential treatments that could halt or slow the devastating effects of the disease. Recently, over-production of Abeta has been shown to result in hyperexcitability and Ca2+ overload in hippocampal and cortical neurons. Increased excitability is also consistent with behavioral studies which have shown enhanced seizure activity in mouse models with increased Abeta expression, and increased risk of epilepsy in AD patients. The goal of this proposal is to determine whether a transgenic Drosophila model that expresses the secreted human Abeta42, which exhibits many of the hallmarks of AD (e.g. Abeta deposits, age-dependent learning/memory and locomotor deficits, neurodegeneration), also displays neuronal hyperexcitability. We will identify how intrinsic electrical properties of neurons are altered, and how these changes affect neuronal excitability. These studies are essential for establishing the Abeta42-Drosophila transgenic line as an effective model for investigations into how Abeta42-induced intrinsic changes, and hyperexcitability, contribute to downstream cellular and behavioral deficits seen AD. Since ion channels are so highly conserved, cellular strategies are likely to be shared across species and findings are expected to be significant for mammalian systems.
Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population. While a large portion of research efforts are directed at understanding the underlying cause(s) of AD, less known about how these events lead to the hallmarks of AD, such as progressive neurodegeneration and a decline in cognitive and motor function. Recent studies have shown that primary events induce hyperexcitability of neurons, although little is known about how this occurs and what the behavioral consequences are. In this proposal, our goal is to understand how primary events of AD change the intrinsic electrical properties of neurons in the brain, and establish a new model for investigating how these changes contribute to downstream phenotypes of AD, including neurodegeneration, and memory and motor dysfunction. With no current cure for AD (prevention of the primary events), understanding the subsequent cellular events that underlie disease progression may give important insight into potential treatments that could halt or slow the devastating effects of the disease.
| Ping, Yong; Hahm, Eu-Teum; Waro, Girma et al. (2015) Linking a?42-induced hyperexcitability to neurodegeneration, learning and motor deficits, and a shorter lifespan in an Alzheimer's model. PLoS Genet 11:e1005025 |
