Pituitary adenylate cyclase–activating polypeptide is reduced in Alzheimer disease

Han, Pengcheng; Liang, Winnie S.; Baxter, Leslie C.; Yin, Jun; Tang, Zhongjia; Beach, Thomas G.; Caselli, Richard J.; Reiman, Eric M.; Shi, Jiong

doi:10.1212/wnl.0000000000000417

Cited by 55 publications

(58 citation statements)

References 8 publications

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“…Han and coworkers measured CSF PACAP levels not only in Alzheimer's disease, but also in other types of dementia, such as Parkinson's disease with dementia and frontotemporal lobar degeneration. In contrast to the signifi cant reduction observed in Alzheimer's disease, no reduction was observed in the CSF of other dementia patients postmortem [ 16 ]. In a family study, where members showed mental retardation, some displaying partial trisomy 18p with three copies of the PACAP gene [ 5 ].…”

Section: Other Dementiasmentioning

confidence: 89%

“…Levels were lower in advanced Braak stages than in moderate stages. Lower PACAP levels were measured in postmortem cisternal cerebrospinal fl uid (CSF) of the same patients parallel with the reduced brain tissue levels [ 16 ]. Additionally, PACAP concentrations in patients with Alzheimer's disease strongly correlated with the dementia rating scores.…”

Section: Alzheimer's Diseasementioning

confidence: 95%

“…The time passed between sample collection and measurement is also critical. Some authors have described PACAP levels in postmortem CSF samples [ 16 ], which obviously cannot be compared to fresh samples taken from patients. Another issue that needs to be taken into consideration is the range within which PACAP levels change.…”

Section: Concluding Remarks: Future Perspectives and Limitationsmentioning

confidence: 99%

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PACAP as a Potential Biomarker: Alterations of PACAP Levels in Human Physiological and Pathological Conditions

Reglődi

Helyes

Németh

et al. 2016

Current Topics in Neurotoxicity

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Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with wide distribution and diverse effects. Its presence has not only been revealed in the nervous system and peripheral organs, but also in the blood and other biological fl uids. Although PACAP is rapidly cleaved in the blood by peptidases, increasing number of evidence has been published in the last 10 years that show alterations of PACAP levels in different pathological conditions. The present review summarizes results obtained in the human blood and other fl uids under normal, physiological and pathological conditions with clinical relevance, such as pregnancy and delivery, as well as in several diseases. Most clinical data have been obtained so far in neurological diseases, such as Alzheimer's disease, migraine, traumatic brain injury, multiple sclerosis, and cerebral hemorrhage, but some other diseases have also been shown to be accompanied by alterations of PACAP levels. These results indicate that the altered levels may have diagnostic and/or prognostic values in several diseases.

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Section: Other Dementiasmentioning

confidence: 89%

Section: Alzheimer's Diseasementioning

confidence: 95%

Section: Concluding Remarks: Future Perspectives and Limitationsmentioning

confidence: 99%

See 1 more Smart Citation

PACAP as a Potential Biomarker: Alterations of PACAP Levels in Human Physiological and Pathological Conditions

Reglődi

Helyes

Németh

et al. 2016

Current Topics in Neurotoxicity

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“…The raw scores from the Mattis Dementia Rating Scale, Stroop Color-Word Interference Test, Auditory Verbal Learning Test–Total Learning (AVLT-TL), and Judgment of Line orientation (JLO), as well as the total number of words learned over trials (new learning) score, were converted to age- and education-corrected z scores. 4 …”

Section: Methodsmentioning

confidence: 99%

“…4 A PACAP deficit was also seen in PS1/APPswe/tauP301L triple transgenic mice. 5 Exogenous PACAP protects neurons from the toxicity of β-amyloid 42 oligomers, which is achieved through increasing sirtuin 3 expression, which in turn enhances mitochondrial function.…”

Section: Introductionmentioning

confidence: 92%

Association of Pituitary Adenylate Cyclase–Activating Polypeptide With Cognitive Decline in Mild Cognitive Impairment Due to Alzheimer Disease

et al. 2015

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IMPORTANCE There is a deficit of pituitary adenylate cyclase-activating polypeptide (PACAP) in patients with neuropathologically confirmed Alzheimer dementia. However, whether this deficit is associated with the earlier stages of Alzheimer disease (AD) is unknown. This study was conducted to clarify the association between PACAP biomarkers and preclinical, mild cognitive impairment (MCI), and dementia stages of AD in postmortem brain tissue.OBJECTIVES To examine PACAP and PACAP receptor levels in postmortem brain tissues and cerebrospinal fluid from cognitively and neuropathologically normal control individuals, patients with MCI due to AD (MCI-AD), and individuals with AD; analyze the relationship between PACAP, cognitive, and pathologic features; and propose a model to assess these relationships. DESIGN, SETTING, AND PARTICIPANTSWe measured PACAP and its receptor (PAC1) levels using enzyme-linked immunoassay. A total of 35 cases were included. All the brain tissue and cerebrospinal fluid samples were selected from Banner Sun Health Research Institute Brain and Body Donation Program. All cognitive test results were in record with the Arizona Alzheimer's Consortium. MAIN OUTCOMES AND MEASURESA comparison of PACAP and PAC1 levels among the healthy controls, MCI-AD, and AD dementia groups, as well as a systematic correlation analysis between PACAP level, cognitive performance, and pathologic severity. RESULTSThe PACAP levels in cerebrospinal fluid, the superior frontal gyrus, and the middle temporal gyrus were inversely related to dementia severity. The PACAP levels in cerebrospinal fluid correlated with the Mattis Dementia Rating Scale score (Pearson r = 0.50; P = .03) and inversely correlated with total amyloid plaques (Pearson r = −0.48; P < .01) and tangles (Pearson r = −0.55; P = .01) in the brain. The PACAP in the superior frontal gyrus and middle temporal gyrus correlated with the Stroop Color-Word Interference Test (Pearson r = 0.58; P < .01) and the Auditory Verbal Learning Test-Total Learning (Pearson r = 0.33; P = .02), respectively. The PACAP in the primary visual cortex did not correlate with the Judgment of Line orientation test (P = .14). Furthermore, the PAC1 level in the superior frontal gyrus showed an upregulation in MCI-AD but not in AD. The pharmacodynamic model of the PACAP-PAC1 interaction best predicted cognitive function in the superior frontal gyrus, but it was less predictive in the middle temporal gyrus and failed to be predictive in the primary visual cortex.CONCLUSIONS AND RELEVANCE Deficits in PACAP are associated with clinical severity in the MCI and dementia stages of AD. Additional studies are needed to clarify the role of PACAP deficits in the predisposition to, pathogenesis of, and treatment of AD.

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Accelerated pre‐senile systemic amyloidosis in PACAP knockout mice – a protective role of PACAP in age‐related degenerative processes

Reglődi

Jungling

Longuespée

et al. 2018

The Journal of Pathology

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Dysregulation of neuropeptides may play an important role in aging‐induced impairments. Among them, pituitary adenylate cyclase‐activating polypeptide (PACAP) is a potent cytoprotective peptide that provides an endogenous control against a variety of tissue‐damaging stimuli. We hypothesized that the progressive decline of PACAP throughout life and the well‐known general cytoprotective effects of PACAP lead to age‐related pathophysiological changes in PACAP deficiency, supported by the increased vulnerability to various stressors of animals partially or totally lacking PACAP. Using young and aging CD1 PACAP knockout (KO) and wild type (WT) mice, we demonstrated pre‐senile amyloidosis in young PACAP KO animals and showed that senile amyloidosis appeared accelerated, more generalized, more severe, and affected more individuals. Histopathology showed age‐related systemic amyloidosis with mainly kidney, spleen, liver, skin, thyroid, intestinal, tracheal, and esophageal involvement. Mass spectrometry‐based proteomic analysis, reconfirmed with immunohistochemistry, revealed that apolipoprotein‐AIV was the main amyloid protein in the deposits together with several accompanying proteins. Although the local amyloidogenic protein expression was disturbed in KO animals, no difference was found in laboratory lipid parameters, suggesting a complex pathway leading to increased age‐related degeneration with amyloid deposits in the absence of PACAP. In spite of no marked inflammatory histological changes or blood test parameters, we detected a disturbed cytokine profile that possibly creates a pro‐inflammatory milieu favoring amyloid deposition. In summary, here we describe accelerated systemic senile amyloidosis in PACAP gene‐deficient mice, which might indicate an early aging phenomenon in this mouse strain. Thus, PACAP KO mice could serve as a model of accelerated aging with human relevance. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Pituitary adenylate cyclase–activating polypeptide is reduced in Alzheimer disease

Abstract: The close relationship between PACAP reduction and the severity of AD pathology suggests that downregulation of PACAP may contribute to AD pathogenesis.

Cited by 55 publications

References 8 publications

PACAP as a Potential Biomarker: Alterations of PACAP Levels in Human Physiological and Pathological Conditions

PACAP as a Potential Biomarker: Alterations of PACAP Levels in Human Physiological and Pathological Conditions

Association of Pituitary Adenylate Cyclase–Activating Polypeptide With Cognitive Decline in Mild Cognitive Impairment Due to Alzheimer Disease

Accelerated pre‐senile systemic amyloidosis in PACAP knockout mice – a protective role of PACAP in age‐related degenerative processes

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