In APP/PS-1 Transgenic Mice and Aβ-Induced P12 Cell Models, ADCYAP1 Inhibits Neuronal Apoptosis and Autophagy, Thereby Alleviating The Pathology of Alzheimer's Disease.

OBJECTIVE: Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly. ADCYAP1 encodes pituitary adenylate cyclase activating polypeptide (PACAP), which can exert neuroprotective effects in neurodegenerative diseases. This study aims to probe the specific function of ADCYAP1 in AD.

MATERIALS AND METHODS: In this experimental study, brain tissue samples from AD patients and healthy controls were collected to assess ADCYAP1 expression. APP/PS-1 transgenic mice were utilised as an AD mouse model along with amyloid beta (Aβ)-induced PC12 cells as an AD cell model. ADCYAP1 expression in the AD mice was determined by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. An IF assay was employed to test Aβ deposition and microtubule-associated protein 2 (MAP2) expression (a neuron marker). Behavioural tests, including the Morris water maze (MWM) and footprint tests, were performed to evaluate cognitive impairment and motor ability. Cell apoptosis was determined using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-nick end labelling (TUNEL) assay. Western blot was utilised to test the expression of autophagy-related genes, including LC3 and beclin1. The expressions of transcription factors involved in neuronal differentiation was assessed by RTqPCR.

RESULTS: ADCYAP1 expression was significantly downregulated in the brain tissues of AD patients and mice. ADCYAP1 overexpression reduced Aβ deposition and enhanced MAP2 expression in the AD mice. ADCYAP1 overexpression effectively improved cognitive impairment and mobility decline in the AD mice. ADCYAP1 upregulation inhibited neuronal apoptosis and autophagy both in vivo and in vitro. ADCYAP1 upregulated the expression of neuronal differentiationrelated factors [transforming growth factor β (TGFβ), early growth response 1 (Egr1), brain-derived neurotrophic factor (BDNF), fibroblast growth factor 21 (FGF21), and insulin-like growth factor 1 (Igf1)] in the AD models.

CONCLUSION: ADCYAP1 inhibits neuronal apoptosis and autophagy to improve AD progression in APP/PS-1 mice and Aβ-induced P12 cells.