title: Pituitary adenylate cyclase-activating polypeptide protects against β-amyloid toxicity.
abstract: Pituitary adenylate cyclase activating polypeptide (PACAP) is a neurotrophin. However, its role in human Alzheimer's disease (AD) is largely unknown. We examined PACAP expression in postmortem human AD and triple transgenic mouse (3xTG, Psen1/APPSwe/TauP301L) brains. We established an in vitro model of primary neuronal cell culture to study the protective effects of PACAP against β-amyloid (Aβ) toxicity. We further studied the PACAP-Sirtuin 3 (Sirt3) pathway on mitochondrial function. PACAP expression was reduced in AD and 3xTG mouse brains. This reduction was inversely correlated with Aβ and tau protein levels. Treatment with PACAP effectively protected neurons against Aβ toxicity. PACAP stimulated mitochondrial Sirt3 production. Similar to PACAP, Sirt3 was reduced in AD and 3xTG brains. Knocking down Sirt3 compromised the neuroprotective effects of PACAP, and this was reversed by over-expressing Sirt3. PACAP is reduced in AD and may represent a novel therapeutic strategy.
authors.affiliation: Department of Neurology, Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Dignity Health Organization, Phoenix, AZ, USA. Electronic address: PengCheng.Han@dignityhealth.org.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Han
authors.affiliation: Department of Neurology, Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Dignity Health Organization, Phoenix, AZ, USA; Department of Neurosurgery, The First Hospital of Kunming Medical University, Kunmming, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Department of Neurology, Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Dignity Health Organization, Phoenix, AZ, USA.
authors.forename: Junxiang
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Neurology, Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Dignity Health Organization, Phoenix, AZ, USA.
authors.forename: Marwan
authors.initials: M
authors.lastname: Maalouf
authors.affiliation: Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.affiliation: Banner Alzheimer's Institute, Phoenix, AZ, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
authors.affiliation: Department of Neurology, Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Dignity Health Organization, Phoenix, AZ, USA. Electronic address: Jiong.Shi@dignityhealth.org.
authors.forename: Jiong
authors.initials: J
authors.lastname: Shi
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000166:cytology* / Q000378:metabolism; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000502:physiology; D058990:Molecular Targeted Therapy; D009414:Nerve Growth Factors; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D056566:Sirtuin 3 / Q000378:metabolism / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D056566:Sirtuin 3
keywords: Alzheimer's disease; Mitochondrial respiration; PACAP; SIRT3