The role of ryanodine receptors in a mouse model of Alzheimer disease

By the year 2020 approximately 1.5 million Canadians will suffer from a form of aging-related dementia, with the majority diagnosed with Alzheimer disease (AD). Current cost estimates suggest that by the year 2025 treatment for neurodegenerative disease will cost the Canadian health care system approximately 50 billion dollars per year. Thus, there is an urgent need for discovery of new therapeutic targets that will delay the onset or reduce the devastating consequences of AD.

The accumulation of amyloid-beta (Aβ) peptide and disruption of cytosolic calcium (Ca2+) levels are pathological hallmarks of neuronal dysfunction in the AD brain. Studies outlined in this thesis focus on the ryanodine receptors (RyRs); how they regulate cytosolic Ca2+ levels and contribute to the dysfunction of AD neurons. RyR type 3 (RyR3) expression was up-regulated when exposed to Aβ fragment 1-42 (Aβ42) and in neurons from transgenic (Tg)CRND8 mice; a model of AD. Ca2+ imaging experiments demonstrated that RyR3 contributed to the increased cytosolic Ca2+ response of Tg to glutamate and ryanodine compared to neurons from nonTg littermates. However, Tg neurons were no more susceptible to AD-related stressors such as glutamate, hydrogen peroxide, staurosporine and in vitro aging. Instead, the suppression of RyR3 up-regulation in Tg neurons by short-interfering RNA sensitized Tg neurons to death after aging in vitro for 18 days. When TgCRND8 mice were crossed with RyR3 knock-out (RyR3-1-) mice, they were sensitized to premature, spontaneous death possibly by severe seizure. TgCRND8/RyR3-1- showed increased susceptibility to more severe, pharmacologically-induced seizure compared to littermates. These data suggest a role for RyR3 in the maintenance of neuronal viability and suppression of hyperexcitability and death in TgCRND8 mice. Further research is required to detemine if RyR3 up-regulation is an optimal therapeutic target for the treatment of AD.