Neurobiol Aging. 2014 Sep;35(9):2064-71. doi: 10.1016/j.neurobiolaging.2014.03.022.

Pituitary adenylate cyclase-activating polypeptide protects against β-amyloid toxicity.

Han P, et al.

Department of Neurology, Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Dignity Health Organization, Phoenix, AZ, USA. Electronic address:



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. Copyright © 2014 Elsevier Inc.

KEYWORDS: Alzheimer’s disease; Mitochondrial respiration; PACAP; SIRT3

PMID: 24726470



PACAP is an acronym for Pituitary Adenylate Cyclase Activating Polypeptide. This molecule was discovered and characterized by Miyata and colleagues 25 years ago1. PACAP was initially isolated from ox pituitary gland, a small organ located on the base of brain. PACAP strongly activates an enzyme called Adenylate Cyclase and facilitates pituitary hormone release (growth hormone,   ACTH, etc). Hence it is named as Pituitary Adenylate Cyclase Activating Polypeptide (PACAP). However, not long after its discovery, the name became archaic because PACAP was found in multiple brain regions beyond pituitary gland.

Thanks to extensive research contributed by multiple groups around the world, we now understand that PACAP is an essential intrinsic peptide that supports the normal development and function of the nervous system.  PACAP knockout mice showed apparent cognitive deficit.  However, there was no direct evidence regarding the implication of PACAP in human Alzheimer’s disease.

Dr. Pengcheng Han and colleagues from St Joseph’s Hospital and Medical Center, Phoenix, AZ, identified a PACAP deficit in postmordem Alzheimer disease brain tissues. This is the first published evidence that implicates PACAP in human Alzheimer’s disease. They further characterized that the severity of PACAP deficit correlates with the last antemortem cognitive test2. Using a systemized transcriptome approach, they discovered that the production of PACAP seems impaired in multiple brain regions of Alzheimer’s patients.

If PACAP is deficient in Alzheimer’s disease, will it be helpful to provide exogenous PACAP?  This is the key question addressed in this highlighted study3. Using Alzheimer disease cell based model, Dr. Han and colleagues discovered that PACAP alleviate β amyloid toxicity, a fundamental culprit for Alzheimer disease.  Furthermore, they conclude that the protective properties of PACAP in Alzheimer pathology could be partially attributed to an improvement of mitochondrial function. Thus, this publication and previous publications from Dr. Han’s group brought a novel insight into the Alzheimer disease research and therapy.


  1. Miyata A, Arimura A, Dahl RR, Minamino N, Uehara A, Jiang L, Culler MD, Coy DH. Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun. 1989 Oct 16;164(1):567-74. PubMed PMID: 2803320.
  2. Han P, Liang W, Baxter LC, Yin J, Tang Z, Beach TG, Caselli RJ, Reiman EM, Shi.J. Pituitary adenylate cyclase-activating polypeptide is reduced in Alzheimer disease. Neurology. 2014 May 13;82(19):1724-8. doi: 10.1212/WNL.0000000000000417.PMID: 24719484; PubMed Central PMCID: PMC4032204.
  3. Han P, Tang Z, Yin J, Maalouf M, Beach TG, Reiman EM, Shi J. Pituitary adenylate cyclase-activating polypeptide protects against β-amyloid toxicity. Neurobiol Aging. 2014 Sep;35(9):2064-71. doi: 10.1016/j.neurobiolaging.2014.03.022. PubMed PMID: 24726470.


Contact for Article reprints:

Pengcheng Han

Dignity Health St Joseph’s Hospital and Medical Center

350 W. Thomas Rd, Phoenix, AZ 85013. Email:

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