A Positive Allosteric Modulator of the SERCA Pump Rescues Hippocampal Neuronal Circuits Dysfunction and Cognitive Defects in a Mouse Model of Alzheimer's Disease

Alzheimer's disease (AD) is a common neurodegenerative disorder that affects normal neuronal functioning and alters neuronal circuits activity and memory formation and storage. Disrupted neuronal calcium (Ca²⁺) signaling is one of the drivers of AD pathogenesis. Previously we suggested that positive allosteric modulators (PAMs) of the sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA) pump may help to stabilize cytosolic Ca²⁺ levels and exert neuroprotective effects in AD neurons. In the current manuscript, we demonstrate synaptoprotective properties of several SERCA PAMs using an in vitro model of amyloid toxicity. Based on in vitro experiments, we selected the SERCA PAM NDC-9009 for in vivo evaluation in male and female 5xFAD transgenic mice model of Alzheimer's disease. Using the miniscope imaging technique, we observed hyperactivity and abnormal connectivity of hippocampal neuronal ensembles 5xFAD mice. We further discovered that the function of the hippocampal neuronal circuits in 5xFAD mice was normalized by NDC-9009 intraperitoneal administration. NDC-9009 intraperitoneal administration also rescued memory defects in 5xFAD mice as quantified by the fear conditioning behavioral test and significantly reduced accumulation of amyloid plaques in hippocampal region of these mice. The obtained results support the potential utility of NDC-9009 and other SERCA PAMs as lead molecules for development of disease-modifying treatments for AD and potentially other neurodegenerative disorders.