Neuroprotective properties of anti-apoptotic BCL-2 proteins in 5xFAD mouse model of Alzheimer’s disease

Alzheimer's disease (AD) is the most common cause of dementia. An early feature of the AD pathology is the dysregulation of intracellular Ca(2+) signaling in neurons. In particular, increased Ca(2+) release from endoplasmic reticulum-located Ca(2+) channels, including inositol-1,4,5-trisphosphate type 1 receptors (IP(3)R1) and ryanodine receptors type 2 (RyR2), have been extensively reported. Known for its anti-apoptotic properties, Bcl-2 also has the ability to bind to and inhibit the Ca(2+)-flux properties of IP(3)Rs and RyRs. In this study, the hypothesis that the expression of Bcl-2 proteins can normalize dysregulated Ca(2+) signaling in a mouse model of AD (5xFAD) and thereby prevent or slow the progression of AD was examined. Therefore, stereotactic injections of adeno-associated viral vectors expressing Bcl-2 proteins were performed in the CA1 region of the 5xFAD mouse hippocampus. In order to assess the importance of the association with IP(3)R1, the Bcl-2(K17D) mutant was also included in these experiments. This K17D mutation has been previously shown to decrease the association of Bcl-2 with IP(3)R1, thereby impairing its ability to inhibit IP(3)R1 while not affecting Bcl-2′s ability to inhibit RyRs. Here, we demonstrate that Bcl-2 protein expression leads to synaptoprotective and amyloid-protective effects in the 5xFAD animal model. Several of these neuroprotective features are also observed by Bcl-2(K17D) protein expression, suggesting that these effects are not associated with Bcl-2-mediated inhibition of IP(3)R1. Potential mechanisms for this Bcl-2 synaptoprotective action may be related to its ability to inhibit RyR2 activity as Bcl-2 and Bcl-2(K17D) are equally potent in inhibiting RyR2-mediated Ca(2+) fluxes. This work indicates that Bcl-2-based strategies hold neuroprotective potential in AD models, though the underlying mechanisms requires further investigation.