Association of Pituitary Adenylate Cyclase–Activating Polypeptide With Cognitive Decline in Mild Cognitive Impairment Due to Alzheimer Disease
Open accessAbstract
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 PARTICIPANTS: We 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 MEASURES: A 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. RESULTS: The 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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Reduced ADCYAP1 in human cerebrospinal fluid and brain specimens has been associated with cognitive decline in mild cognitive impairment due to Alzheimer's disease.
“reduced ADCYAP1 in human CSF and brain specimens has been associated with cognitive decline in mild cognitive impairment due to AD40”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [40]
Some of these molecules have been linked in prior work to memory impairment and to mild cognitive impairment in AD.
“Defects in some of these molecules have been implicated in impaired memory39 and associated with mild cognitive impairment in AD40.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [40]
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Cites
Miyata, A., Arimura, A., Dahl, R. R., Minamino, N., Uehara, A., Jiang, L., Culler, M. D., & Coy, D. H. (1989) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(89)91757-9 · Cited by 1,831 · see citing works
HYMAN, B. T., & TROJANOWSKI, J. Q. (1997) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199710000-00002 · Cited by 1,542 · see citing works
Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease
Lue, L.-F., Kuo, Y.-M., Roher, A. E., Brachova, L., Shen, Y., Sue, L., Beach, T., Kurth, J. H., Rydel, R. E., & Rogers, J. (1999) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65184-x · Cited by 1,530 · see citing works
Self-citationThe foundations of chemical kinetics
Benson, S. W. (1960) · Journal of the Franklin Institute · doi:10.1016/0016-0032(60)90305-7 · Cited by 1,458 · see citing works
Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: From Structure to Functions
Vaudry, D., Gonzalez, B. J., Basille, M., Yon, L., Fournier, A., & Vaudry, H. (2000) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01449-2 · Cited by 1,120 · see citing works
Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery
Vaudry, D., Falluel‐Morel, A., Bourgault, S., Basille, M., Burel, D., Wurtz, O., Fournier, A., Chow, B., Hashimoto, H., Galas, L., et al. (2009) · Pharmacological Reviews · doi:10.1124/pr.109.001370 · Cited by 1,060 · see citing works
Li, R., Lindholm, K., Yang, L., Yue, X., Citron, M., Yan, R., Beach, T. G., Sue, L. I., Sabbagh, M. N., Cai, H., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0205689101 · Cited by 493 · see citing works
Self-citationMRI and CSF biomarkers in normal, MCI, and AD subjects
Vemuri, P., Wiste, H. J., Weigand, S. D., Shaw, L. M. J., Trojanowski, J. Q., Weiner, M. W., Knopman, D. S., Petersen, R. C., & Jack, C. R. (2009) · Neurology · doi:10.1212/wnl.0b013e3181af79fb · Cited by 398 · see citing works
Neurophysiology of HCN channels: From cellular functions to multiple regulations
He, C., Chen, F., Li, B., & Hu, Z. (2013) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.10.001 · Cited by 351 · see citing works
A Neuropeptide Gene Defined by the Drosophila Memory Mutant amnesiac
Feany, M. Β., & Quinn, W. G. (1995) · Science · doi:10.1126/science.7754370 · Cited by 269 · see citing works
MRI and CSF biomarkers in normal, MCI, and AD subjects
Vemuri, P., Wiste, H. J., Weigand, S. D., Shaw, L. M. J., Trojanowski, J. Q., Weiner, M. W., Knopman, D. S., Petersen, R. C., & Jack, C. R. (2009) · Neurology · doi:10.1212/wnl.0b013e3181af79e5 · Cited by 246 · see citing works
Early Diagnosis of Alzheimers Disease: Is MCI Too Late?
Petersen, R. C. (2009) · Current Alzheimer Research · doi:10.2174/156720509788929237 · Cited by 239 · see citing works
Rat, D., Schmitt, U., Tippmann, F., Dewachter, I., Theunis, C., Wieczerzak, E., Postina, R., LEUVEN, F. V., Fahrenholz, F., & Kojro, E. (2011) · The FASEB Journal · doi:10.1096/fj.10-180133 · Cited by 148 · see citing works
Macdonald, D. S., Weerapura, M., Beazely, M. A., Martin, L. J., Czerwinski, W., Roder, J., Orser, B. A., & MacDonald, J. F. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.3871-05.2005 · Cited by 115 · see citing works
Pituitary adenylate cyclase-activating polypeptide protects against β-amyloid toxicity
Han, P., Tang, Z., Yin, J., Maalouf, M., Beach, T. G., Reiman, E. M., & Shi, J. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.03.022 · Cited by 110 · see citing works
Self-citationFilippi, M., & Agosta, F. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-101854 · Cited by 89 · see citing works
Regulation of glutamatergic signalling by PACAP in the mammalian suprachiasmatic nucleus
Michel, S. H., Itri, J. N., Han, J. H., Gniotczynski, K., & Colwell, C. S. (2006) · BMC Neuroscience · doi:10.1186/1471-2202-7-15 · Cited by 80 · cited 1× · see citing works
“(%) Male 8 (80) 4 (44) 7 (44) Female 2 (20) 5 (56) 9 (56) Age, mean (SD), y 86.”
Intranasal administration of PACAP: Uptake by brain and regional brain targeting with cyclodextrins
Nonaka, N., Farr, S. A., Nakamachi, T., Morley, J. E., Nakamura, M., Shioda, S., & Banks, W. A. (2012) · Peptides · doi:10.1016/j.peptides.2012.05.021 · Cited by 75 · see citing works
Pituitary adenylate cyclase–activating polypeptide is reduced in Alzheimer disease
Han, P., Liang, W. S., Baxter, L. C., Yin, J., Tang, Z., Beach, T. G., Caselli, R. J., Reiman, E. M., & Shi, J. (2014) · Neurology · doi:10.1212/wnl.0000000000000417 · Cited by 64 · see citing works
Self-citationImaging and Biomarkers in Early Alzheimer's Disease and Mild Cognitive Impairment
Petersen, R. C., & Jack, C. R. (2009) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2009.166 · Cited by 56 · see citing works
Han, P., & Lucero, M. T. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2005.11.028 · Cited by 31 · see citing works
Self-citationHan, P., & Lucero, M. T. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.05.007 · Cited by 31 · see citing works
Self-citationPirger, Z., László, Z., Hiripi, L., Hernádi, L., Tóth, G. K., Lubics, A., Reglődi, D., Kemenes, G., & Márk, L. (2010) · Journal of Molecular Neuroscience · doi:10.1007/s12031-010-9361-x · Cited by 30 · see citing works
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Cited by
Sorted by citations
Zhou, Y., Song, W. M., Andhey, P. S., Swain, A., Levy, T., Miller, K. R., Poliani, P. L., Cominelli, M., Grover, S., Gilfillan, S., et al. (2020) · Nature Medicine · doi:10.1038/s41591-019-0695-9 · Cited by 1,150 · see citing works
Detection of Alzheimer’s disease by displacement field and machine learning
Zhang, Y., & Wang, S. (2015) · PeerJ · doi:10.7717/peerj.1251 · Cited by 126 · see citing works
“Table 6 shows that the displacement field finds the discriminant associated with the following regions reported in latest references: Angular Gyrus (Carbonell et al., 2014), Anterior Cingulate (Schultz et al., 2014), Cingulate Gyrus (Yu et al., 2014), Culmen (Almeida et al., 2011), Cuneus (Yokoyama et al., 2015), Fusi…”
BackgroundInfluentialWang, S., Zhang, Y., Liu, G., Phillips, P., & Yuan, T. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-150848 · Cited by 112 · see citing works
“[79] Precentral Gyrus (BA-3, 4) 175 Wang et al.”
BackgroundPiras, I. S., Krate, J., Delvaux, E., Nolz, J., Mastroeni, D., Persico, A. M., Jepsen, W. M., Beach, T. G., Huentelman, M. J., & Coleman, P. D. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-181113 · Cited by 98 · see citing works
Self-citationPACAP deficiency as a model of aging
Reglődi, D., Atlasz, T., Szabó, E., Jüngling, A., Tamás, A., Juhász, T., Fulop, B. D., & Bardosi, A. (2018) · GeroScience · doi:10.1007/s11357-018-0045-8 · Cited by 57 · see citing works
Dénes, V., Geck, P., Mester, A., & Gabriel, R. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8091488 · Cited by 58 · see citing works
“In several studies, PACAP1-38 gene expression, protein levels, and the PAC1-R receptor were downregulated in both mouse models and postmortem human brain samples, which indicates correlations between PACAP1-38 levels and disease progression [82,83,211].”
BackgroundSolés-Tarrés, I., Cabezas-Llobet, N., Vaudry, D., & Xifró, X. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00221 · Cited by 55 · see citing works
Neuropeptides in Alzheimer’s Disease: An Update
Petrella, C., Certo, M. G. D., Barbato, C., Gabanella, F., Ralli, M., Greco, A., Possenti, R., & Severini, C. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190503152555 · Cited by 53 · see citing works
Wu, Y., & Angelova, A. (2023) · Nanomaterials · doi:10.3390/nano13233004 · Cited by 53 · see citing works
Cabezas-Llobet, N., Vidal-Sancho, L., Masana, M., Fournier, A., Alberch, J., Vaudry, D., & Xifró, X. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-0972-5 · Cited by 48 · see citing works
“Consistently, studies in humans revealed that a decrease of PACAP levels is associated with severity [34] and cognitive impairment [54] in AD.”
Lu, J., Piper, S. J., Zhao, P., Miller, L. J., Wootten, D. L., & Sexton, P. M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158069 · Cited by 46 · see citing works
“PAC1R CNS [35] (olfactory bulb [16,73], cerebral cortex, thalamus [73], hypothalamus [73,74], hippocampus, amygdala [73,75], substantia nigra [73], cerebellum [73] Astrocyte proliferation [76], appetite and feeding behaviour [77,78], anxiety [79], stress response [80–82], control of circadian rhythm [20], post-traumat…”
BackgroundBose, M., Quipildor, G. F., Ehrlich, M. E., & Salton, S. R. (2022) · Cells · doi:10.3390/cells11223629 · Cited by 44 · see citing works
A Quantitative Analysis of Brain Soluble Tau and the Tau Secretion Factor
Han, P., Serrano, G. E., Beach, T. G., Caselli, R. J., Yin, J., Zhuang, N., & Shi, J. (2017) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlw105 · Cited by 44 · see citing works
Self-citationReglődi, D., Jüngling, A., Longuespée, R., Kriegsmann, J., Casadonte, R., Kriegsmann, M., Juhász, T., Bardosi, S., Tamás, A., Fulop, B. D., et al. (2018) · The Journal of Pathology · doi:10.1002/path.5100 · Cited by 38 · see citing works
“PACAP levels decline with age in humans and experimental animals [71], as shown in rhesus monkey and post-mortem human brains of Alzheimer’s patients and in cognitive decline preceding the disease [22,23,72,73], with an association between PACAP levels and disease scores.”
BackgroundThe Neuroprotective and Biomarker Potential of PACAP in Human Traumatic Brain Injury
Tóth, D., Tamás, A., & Reglődi, D. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21030827 · Cited by 34 · see citing works
“CSF PACAP levels are decreased in Alzheimer’s disease [39,40] and multiple sclerosis [57].”
BackgroundKorkmaz, O. T., Ay, H., Aytan, N., Carreras, I., Kowall, N. W., Dedeoglu, A., & Tunçel, N. (2018) · Journal of Molecular Neuroscience · doi:10.1007/s12031-018-1226-8 · Cited by 31 · see citing works
Review on PACAP-Induced Transcriptomic and Proteomic Changes in Neuronal Development and Repair
Rivnyak, A., Kiss, P., Tamás, A., Balogh, D., & Reglődi, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19041020 · Cited by 29 · see citing works
“Recent results indicate that this effect of PACAP is not only present in animal models but is also implicated in human diseases, in acute and chronic neuronal pathological conditions, and endogenous decline of the peptide can indicate neuronal degeneration [11].”
BackgroundA Theoretical Analysis of the Synergy of Amyloid and Tau in Alzheimer’s Disease
Han, P., & Shi, J. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-151206 · Cited by 29 · see citing works
“We have used this cohort to conduct other studies [20].”
Self-citationCiranna, L., & Costa, L. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00524 · Cited by 28 · see citing works
Owona, B. A., Zug, C., Schluesener, H. J., & Zhang, Z. (2016) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlw043 · Cited by 26 · see citing works
“Decreased AC levels have recently been reported in CSF and postmortem brain tissue samples from patients suffering from dementia (6).”
BackgroundBiran, J., Gliksberg, M., Shirat, I., Swaminathan, A., Levitas‐Djerbi, T., Appelbaum, L., & Levkowitz, G. (2020) · Scientific Reports · doi:10.1038/s41598-020-66447-2 · Cited by 22 · see citing works
Zheng, R., Zhang, Z.-H., Zhao, Y., Chen, C., Jia, S.-Z., Cao, X.-C., Shen, L., Ni, J., & Song, G.-L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20122998 · Cited by 22 · see citing works
“This work has identified several key genes upregulated after treatment with Se-Met, including Adcyap1, which encodes a member of the glucagon superfamily of hormones that have important roles in the pathogenesis of AD [33].”
BackgroundReglődi, D., Helyes, Z., Németh, J., Vass, R. A., & Tamás, A. (2016) · Current topics in neurotoxicity · doi:10.1007/978-3-319-35135-3_48 · Cited by 21 · see citing works
Fehér, M., Gaszner, B., Tamás, A., Gil-Martínez, A. L., Fernández‐Villalba, E., Herrero, M. T., & Reglődi, D. (2017) · Neurotoxicity Research · doi:10.1007/s12640-017-9841-7 · Cited by 21 · see citing works
Wei, K., Kong, W., & Wang, S. (2021) · Journal of Molecular Neuroscience · doi:10.1007/s12031-021-01888-6 · Cited by 19 · see citing works
“2015), middle temporal gyrus (Han et al. 2015), precuneus (Villeneuve et al.”
BackgroundAvila, J. A., Kiprowska, M., Jean-Louis, T. L., Rockwell, P., Figueiredo‐Pereira, M. E., & Serrano, P. A. (2019) · Brain and Behavior · doi:10.1002/brb3.1465 · Cited by 16 · see citing works
“Interestingly, PACAP levels are reduced in humans with AD which is correlated with both cognitive decline and severity of pathologic marker expression (Han et al., 2015).”
BackgroundAvolio, E., Fazzari, G., Mele, M., Alò, R., Zizza, M., Jiao, W., Vito, A. D., Barni, T., Mandalà, M., & Canonaco, M. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0171-1 · Cited by 18 · see citing works
“For this reason, our attention was focused on establishing if endothelial damages were linked with the maintenance of DEP through neurodegenerative events in AMY, HIP, and PFC, which are largely involved with cognitive decline following the onset of DEP states [17, 18].”
BackgroundInfluentialBardosi, S., Bardosi, A., Nagy, Z., & Reglődi, D. (2016) · Journal of Molecular Neuroscience · doi:10.1007/s12031-016-0823-7 · Cited by 17 · see citing works
The Potential of the Nose-to-Brain Delivery of PACAP for the Treatment of Neuronal Disease
Cherait, A., Banks, W. A., & Vaudry, D. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15082032 · Cited by 16 · see citing works
Potashkin, J. A., Bottero, V., Santiago, J. A., & Quinn, J. P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21113787 · Cited by 16 · see citing works
“In order to identify key regulators of switch genes obtained from AD, VaD, and FTD, gene transcription factors, interactomes were performed using NetworkAnalyst [22] with the ENCODE, JASPAR, and ChEA databases.”
BackgroundMethodSun, B., Sun, Z.-P., Pang, Z.-C., Huang, W.-T., & Wu, S.-P. (2019) · Peptides · doi:10.1016/j.peptides.2019.04.009 · Cited by 14 · see citing works
PACAP: A promising disease-modifying target for Alzheimer's disease
Basri, R., Al-Kuraishy, H. M., Fawzy, M. N., Alruwaili, M., & Batiha, G. E. (2025) · Life Sciences · doi:10.1016/j.lfs.2025.124176 · Cited by 13 · see citing works
Pituitary adenylate cyclase-activating polypeptide: Protective effects in stroke and dementia
Nonaka, N., Banks, W. A., & Shioda, S. (2020) · Peptides · doi:10.1016/j.peptides.2020.170332 · Cited by 13 · see citing works
Pham, D., Polgár, B., Toth, T., Jüngling, A., Kovács, N., Balás, I., Pál, E., Szabo, D., Fulop, B. D., Reglődi, D., et al. (2022) · GeroScience · doi:10.1007/s11357-022-00530-6 · Cited by 13 · see citing works
Role of endocrine PACAP in age-related diseases
Tóth, D., Reglődi, D., Schwieters, L., & Tamás, A. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1118927 · Cited by 13 · see citing works
“Furthermore, it was found that PAC1 expression in the superior frontal gyrus showed an upregulation in mild cognitive impairment due to AD but not in AD without dementia (28).”
BackgroundHan, P., Nielsen, M., Song, M., Yin, J., Permenter, M. R., Vogt, J. A., Engle, J. R., Dugger, B. N., Beach, T. G., Barnes, C. A., et al. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00180 · Cited by 12 · see citing works
“PACAP is reduced in brains of AD patients (Han et al., 2015) and 18-month old 3×Tg AD mice (Han et al., 2014b), so we measured cerebral PACAP levels in different age groups of hAPP mice (Figure 5F).”
BackgroundInfluentialSelf-citationIntegrated analysis of the lncRNA-associated ceRNA network in Alzheimer's disease
Cai, H.-Y., Chen, S., Wang, Y., Jiao, J., Qiao, J., Hölscher, C., Wang, Z., Zhang, S., & Wu, M. (2023) · Gene · doi:10.1016/j.gene.2023.147484 · Cited by 11 · see citing works
Tamás, A., Tóth, D., Pham, D., Loibl, C., Rendeki, S., Csontos, C., Rozanovic, M., Bogár, L., Polgár, B., Németh, J., et al. (2021) · Peptides · doi:10.1016/j.peptides.2021.170645 · Cited by 8 · see citing works
Tambo, W., Powell, K., Wadolowski, S., Unadkat, P., Chang, E. H., LeDoux, C., Sciubba, D. M., Wang, P., Huerta, P. T., & Li, C. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70925 · Cited by 7 · see citing works
Guo, X., Li, J., Qi, Y., Chen, J., Jiang, M., Zhu, L., Liu, Z., Wang, H., Wang, G.-W., & Wang, X. (2024) · Aging Cell · doi:10.1111/acel.14121 · Cited by 6 · see citing works
“…focus on these tissues were as follows: (i) Although hippocampus is a well-known tissue highly relevant to AD pathogenesis, the degeneration of prefrontal cortex, cerebellum, and pituitary gland is also involved in neuropathology of AD (Bossers et al., 2010; Han et al., 2015; Jacobs et al., 2018).”
BackgroundYu, R., Lin, Z., Ouyang, Z., Tao, Z., & Fan, G. (2021) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2021.129884 · Cited by 6 · see citing works
Futran-Sheinberg, E. J., Urbina, V., Nava, S., Sanchez, D., Guzmán-Valdivia, G., & Zetter, M. A. (2025) · Neuroglia · doi:10.3390/neuroglia6030035 · Cited by 4 · see citing works
“Similarly, patients with neuropathologically confirmed Alzheimer dementia have reduced levels of PACAPs and VIPs in cerebrospinal fluid and brain expression in cortical structures [38].”
PACAP Regulation of Inflammatory and Free Radical Networks in Neuronal and Nonneuronal Diseases
Ohtaki, H., & Shioda, S. (2016) · Current topics in neurotoxicity · doi:10.1007/978-3-319-35135-3_39 · Cited by 5 · see citing works
Sparks, J., Jüngling, A., Kiss, G., Hiripi, L., Pham, D., Tamás, A., Hoffmann, O. I., Bardosi, S., Miseta, A., & Reglődi, D. (2021) · Applied Sciences · doi:10.3390/app11167373 · Cited by 5 · see citing works
Gopalakrishna, R., Lin, C. Y. H., Oh, A., Le, C., Yang, S., Hicks, A., Kindy, M. S., Mack, W. J., & Bhat, N. R. (2022) · FEBS Letters · doi:10.1002/1873-3468.14467 · Cited by 4 · see citing works
Mechanisms of PACAP in PTSD and Stress-Related Disorders in Humans
Lebois, L. A. M., & Ressler, K. J. (2016) · Current topics in neurotoxicity · doi:10.1007/978-3-319-35135-3_45 · Cited by 4 · see citing works
Tóth, D., Veszprémi, B., Koppán, M., Tamás, A., Szogyi, D., Brubel, R., Németh, J., Shams, M., & Reglődi, D. (2020) · Reproductive Biology · doi:10.1016/j.repbio.2020.07.013 · Cited by 3 · see citing works
GPCR-mediated clearance of tau in post-synaptic compartments attenuates tau pathology in vivoPreprint
Schaler, A. W., Runyan, A. M., Fowler, S. L., Figueroa, H. Y., Shioda, S., Santa‐María, I., Duff, K., & Myeku, N. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.01.21.914135 · Cited by 2 · see citing works
Hassan, M. E., Al‐kuraishy, H. M., Fawzy, M. N., Hussain, N. R., Al-Gareeb, A. I., Rashwan, E. K., Albuhadily, A. K., & Batiha, G. E. (2026) · Neuropharmacology · doi:10.1016/j.neuropharm.2026.111013 · Cited by 1 · see citing works
Sharma, R., Shkirkova, K., Mack, W. J., & Gopalakrishna, R. (2026) · Journal of dementia and Alzheimer's disease · doi:10.3390/jdad3020027 · Cited by 1 · see citing works
“The cAMP-elevating neuroprotective peptide, pituitary adenylyl cyclase-activating polypeptide (PACAP), protects neurons from A β oligomer (A β O)-induced cell death [202]; however, PACAP levels are reduced in AD patients relative to age-matched controls [203].”
Effects and Development of TAT-Tagged PACAP/VIP and Related Peptides
Yu, R. (2016) · Current topics in neurotoxicity · doi:10.1007/978-3-319-35135-3_10
Identification and validation of PANoptosis-related genes in Alzheimer's disease
Zhou, W., Lin, H., Huang, X., & Zhou, X. (2025) · Journal of Alzheimer s Disease · doi:10.1177/13872877251396927
“32,33 However, in this study, ADCYAP1 is downregulated.”
Su, W., Xiao, L., Tang, S., Zheng, X., Zhang, Y., & Yu, R. (2026) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2026032
Impaired peptide amidation and risk of incident dementia in the Malmoe preventive project cohort
Kaufmann, P., Ilina, Y., Giontella, A., Press, M., Nägga, K., Hansson, O., Hampel, H. J., Bergmann, A., & Melander, O. (2026) · Alzheimer s Research & Therapy · doi:10.1186/s13195-026-02173-7
“In AD, reduced levels of several amidated peptides, including PACAP, Substance P and NPY, have been reported, suggesting a common deficit in neuropeptide signalling [12, 13, 25].”
- Authors
- Han, P., Caselli, R. J., Baxter, L., Serrano, G., Yin, J., Beach, T. G., Reiman, E. M., & Shi, J.
- Affiliations
- Barrow Neurological Institute (US)
- Mayo Clinic (US)
- Banner Sun Health Research Institute (US)
- Banner Alzheimer’s Institute (US)
- Corresponding author
- Shi, Jiong
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2015-03-01
- Volume
- 72
- Issue
- 3
- Pages
- 333
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC5924703
- OpenAlex
- W2032994377
- Cited by
- 55
- References
- 23
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 1 · 2023: 4 · 2022: 4 · 2021: 4 · 2020: 8 · 2019: 7 · 2018: 6 · 2017: 3 · 2016: 8 · 2015: 2
- FWCI
- 5.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P30-AG-19610, P30AG019610)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- pituitary adenylate cyclase-activating polypeptide, PACAP, PAC1 receptor, Alzheimer's disease, mild cognitive impairment, cognitive decline, cerebrospinal fluid biomarkers, amyloid plaques, neurofibrillary tangles, dementia severity, postmortem brain, superior frontal gyrus, middle temporal gyrus, preclinical Alzheimer's disease, neuroinflammation
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Cross-Sectional Studies, Female, Humans, Male, Biomarkers, Pituitary Adenylate Cyclase-Activating Polypeptide, Cognitive Dysfunction
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