PACAP: A promising disease-modifying target for Alzheimer's disease.

Alzheimer's disease (AD) is a significant public health threat, and current therapeutic approaches provide only minimal symptomatic benefit without slowing its progression. This review covers evidence for the expanding involvement of pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenous neuropeptide with significant and consistent neuroprotective properties in various experimental models of AD. We consolidate evidence that PACAP works via multiple pathways to negate primary pathological events in AD by shifting the metabolism of amyloid precursor protein from the amyloidogenic into non-amyloidogenic, inhibiting tau hyperphosphorylation, controlling neuroinflammation, and promoting synaptic plasticity. The reduced level of PACAP in clinical studies of AD patients supports its therapeutic relevance. Although concerns about PACAP pharmacokinetics and blood-brain barrier (BBB) penetration persist as serious obstacles, recent development of stable analogs and innovative delivery systems holds promise for circumventing these limitations. We also consider how established drugs (metformin, linagliptin, and statins) might provide a degree of neuroprotection in part-seeking through PACAP-related pharmacology. Taken together, the cumulative available evidence places PACAP not only as yet another promising therapeutic candidate but rather as a master regulator of neuroprotection, tackling AD's multifaceted nature. Restoration of PACAP signaling is a very distinct method to intervene in disease development, which offers immeasurable benefit in comparison to symptom relief treatment.