Pituitary adenylate cyclase-activating polypeptide is reduced in Alzheimer disease.
OBJECTIVE
There is growing evidence that pituitary adenylate cyclase-activating polypeptide (PACAP) is associated with Alzheimer disease (AD) pathology in animal models, but human studies are needed.


METHODS
We studied the brains of patients with pathologically confirmed late-onset AD and age-matched cognitively normal (CN) subjects to investigate the expression of PACAP messenger RNA (34 AD and 14 CN) and protein (12 AD and 11 CN) in a case-control study.


RESULTS
We report that PACAP levels are reduced in multiple brain regions, including the entorhinal cortex, the middle temporal gyrus, the superior frontal gyrus, and the primary visual cortex. This reduction is correlated with higher amyloid burden (CERAD plaque density) in the entorhinal cortex and superior frontal gyrus but not in the primary visual cortex, a region spared in most cases of AD. PACAP expression is lower in advanced Braak stages (V and VI) than in moderate stages (III and IV). Increased PACAP levels are associated with decreased scores on the Dementia Rating Scale, a global cognitive measure. Finally, CSF levels paralleled brain levels in AD but not in Parkinson dementia or frontotemporal dementia brains.


CONCLUSIONS
The close relationship between PACAP reduction and the severity of AD pathology suggests that downregulation of PACAP may contribute to AD pathogenesis.
From the Barrow Neurological Institute (P.H., L.C.B., J.Y., Z.T., J.S.), St. Joseph Hospital and Medical Center, Dignity Health Organization, Phoenix; Translational Genomics Research Institute (W.L.), Phoenix, AZ; Department of Neurosurgery (Z.T.), The First Hospital of Kunming Medical University, Kunming, China; Civin Laboratory for Neuropathology (T.G.B.), Banner Sun Health Research Institute, Sun City; Department of Neurology (R.J.C.), Mayo Clinic Arizona, Scottsdale; and Banner Alzheimer's Institute (E.M.R.), Phoenix, AZ.
Pengcheng
P
Han
Winnie
W
Liang
Leslie C
LC
Baxter
Junxiang
J
Yin
Zhiwei
Z
Tang
Thomas G
TG
Beach
Richard J
RJ
Caselli
Eric M
EM
Reiman
Jiong
J
Shi
D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D015536:Down-Regulation; D057180:Frontotemporal Dementia / Q000134:cerebrospinal fluid; D006801:Humans; D010300:Parkinson Disease / Q000134:cerebrospinal fluid; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000134:cerebrospinal fluid / Q000172:deficiency*; D058225:Plaque, Amyloid / Q000378:metabolism; D012720:Severity of Illness Index
D051219:Pituitary Adenylate Cyclase-Activating Polypeptide