While, the mechanism(s) underlying Alzheimer’s Disease (AD) remain obscure, hindering the development of
novel effective therapy, there is general consensus that calcium (Ca2+) plays a role. Our hypothesis is that
adrenergic and oxidative stress cause a leak in intracellular Ca2+ release channels/ryanodine receptors (RyR2)
in neurons resulting in AD neuropathology and cognitive dysfunction. In support of this hypothesis others have
shown that dantrolene, which acts on RyR channels, improves cognitive function and reduces Aβ plaques in
AD mice. However, more work is needed because the mechanisms causing RyR2 dysfunction and their
correlation with abnormal intracellular Ca2+ handling and Aβ plaques in AD remain elusive. We have
demonstrated that leaky RyR2 channels in the brain, caused by PKA hyperphosphorylation, oxidation/S-
nitrosylation, and depletion of the stabilizing subunit calstabin2 from the channel, play a key role in stress-
induced cognitive dysfunction using a chronic restraint stress murine model of PTSD with significant cognitive
dysfunction (Liu et al, Cell 2012). The stress-induced cognitive dysfunction was rescued either by
administering S107, a novel Rycal developed in the PIs laboratory that stabilizes RyR-calstabin interactions
and prevents intracellular Ca2+ leak, or by genetic ablation of the RyR2 PKA phosphorylation site at Ser2808
(S2808) in mice (RyR2-S2808A+/+ knock-in), implicating leaky RyR2 and adrenergic signaling in the etiology
of AD associated cognitive dysfunction. Our new preliminary data show that RyR2 channels in the human AD
patient brains and in three murine models of familial Alzheimer’s Disease (FAD), are PKA hyperphosphorylated,
oxidized/S-nitrosylated, and depleted of the stabilizing subunit calstabin2, a biochemical “signature” that
denotes a pathological intracellular Ca2+ leak. Preventing RyR2 leak BOTH genetically or pharmacologically
normalizes Ca2+ signaling, reduces amyloid plaque formation in APP+/-/PS1+/- and in 3XTg-AD
(APPswe/PS1Psen1/TauP301L) mice, and improves learning and memory as well as long-term potentiation (LTP)
and long-term depression (LTD). Using a genetic approach we show that knock-in mice with leaky RyR2
channels (RyR2-S2808D+/+ knock-in) have leaky hippocampal RyR2 and premature cognitive dysfunction.
The aims are: Aim 1) RyR-mediated pathological calcium dysregulation in AD: identify upstream signals. Aim 2)
RyR mediated pathological calcium dysregulation in AD: identify downstream signals. Aim 3) Determine key
calcium dependent mechanisms in AD pathogenesis.