Neuropeptide pituitary adenylate cyclase‐activating polypeptide (PACAP) slows down Alzheimer's disease‐like pathology in amyloid precursor protein‐transgenic mice

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) has neuroprotective and neurotrophic properties and is a potent α-secretase activator. As PACAP peptides and their specific receptor PAC1 are localized in central nervous system areas affected by Alzheimer's disease (AD), this study aims to examine the role of the natural peptide PACAP as a valuable approach in AD therapy. We investigated the effect of PACAP in the brain of an AD transgenic mouse model. The long-term intranasal daily PACAP application stimulated the nonamyloidogenic processing of amyloid precursor protein (APP) and increased expression of the brain-derived neurotrophic factor and of the antiapoptotic Bcl-2 protein. In addition, it caused a strong reduction of the amyloid β-peptide (Aβ) transporter receptor for advanced glycation end products (RAGE) mRNA level. PACAP, by activation of the somatostatin-neprilysin cascade, also enhanced expression of the Aβ-degrading enzyme neprilysin in the mouse brain. Furthermore, daily PAC1-receptor activation via PACAP resulted in an increased mRNA level of both the PAC1 receptor and its ligand PACAP. Our behavioral studies showed that long-term PACAP treatment of APP[V717I]-transgenic mice improved cognitive function in animals. Thus, nasal application of PACAP was effective, and our results indicate that PACAP could be of therapeutic value in treating AD.—Rat, D., Schmitt, U., Tippmann, F., Dewachter, I., Theunis, C., Wieczerzak, E, Postina, R., van Leuven, F., Fahrenholz, F., Kojro, E. Neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) slows down Alzheimer's disease-like pathology in amyloid precursor protein-transgenic mice.

Intranasal Delivery of Proteins and Peptides in the Treatment of Neurodegenerative Diseases

“…The levels observed in the brain after intranasal administration are capable of exerting an effect on CNS function as observed after treatment of SAMP8 mice. In addition, daily intranasal treatment of PACAP for 3 months in another genetic AD mouse model, APP[V717I] transgenic mice, altered APP processing by increasing secretion of the neuroprotective sAPPα and improved cognition (31).…”

Pituitary adenylate cyclase–activating polypeptide is reduced in Alzheimer disease

“…2 Recent studies demonstrate that PACAP can stimulate nonamyloidogenic processing, inhibit amyloid deposition, facilitate b-amyloid clearance, and improve cognitive performance in amyloid precursor protein transgenic mice. 3 PACAP can also promote synaptic transmission, long-term potentiation, and memory performance under physiologic conditions. 4 However, the relevance of PACAP expression has not been studied in the human AD brain.…”

Pituitary Adenylate Cyclase Activating Polypeptide Elicits Neuroprotection Against Acute Ischemic Neuronal Cell Death Associated with NMDA Receptors

“…1). PACAP-27/38 is related to cell growth pathways [18] and anti-inflammatory signaling [9,10], suggesting its potential application in the treatment of neuronal diseases [19]. However, PACAP-27/38 administration did not alter cell growth (Fig.…”