Cholecystokinin (CCK): a neuromodulator with therapeutic potential in Alzheimer's and Parkinson's disease

Cholecystokinin (CCK) is a neuropeptide modulating digestion, glucose levels, neurotransmitters and memory. Recent studies suggest that CCK exhibits neuroprotective effects in Alzheimer's disease (AD) and Parkinson's disease (PD). Thus, we review the physiological function and therapeutic potential of CCK. The neuropeptide facilitates hippocampal glutamate release and gates GABAergic basket cell activity, which improves declarative memory acquisition, but inhibits consolidation. Cortical CCK alters recognition memory and enhances audio-visual processing. By stimulating CCK-1 receptors (CCK-1Rs), sulphated CCK-8 elicits dopamine release in the substantia nigra and striatum. In the mesolimbic pathway, CCK release is triggered by dopamine and terminates reward responses via CCK-2Rs. Importantly, activation of hippocampal and nigral CCK-2Rs is neuroprotective by evoking AMPK activation, expression of mitochondrial fusion modulators and autophagy. Other benefits include vagus nerve/CCK-1R-mediated expression of brain-derived neurotrophic factor, intestinal protection and suppression of inflammation. We also discuss caveats and the therapeutic combination of CCK with other peptide hormones.