Accelerated retinal aging in PACAP knock-out mice

Abstract

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neurotrophic and neuroprotective peptide. PACAP and its receptors are widely distributed in the retina. A number of reports provided evidence that PACAP is neuroprotective in retinal degenerations. The current study compared retina cell type-specific differences in young (3-4months) and aged adults (14-16months), of wild-type (WT) mice and knock-out (KO) mice lacking endogenous PACAP production during the course of aging. Histological, immunocytochemical and Western blot examinations were performed. The staining for standard neurochemical markers (tyrosine hydroxylase for dopaminergic cells, calbindin 28 kDa for horizontal cells, protein kinase Cα for rod bipolar cells) of young adult PACAP KO retinas showed no substantial alterations compared to young adult WT retinas, except for the specific PACAP receptor (PAC1-R) staining. We could not detect PAC1-R immunoreactivity in bipolar and horizontal cells in young adult PACAP KO animals. Some other age-related changes were observed only in the PACAP KO mice only. These alterations included horizontal and rod bipolar cell dendritic sprouting into the photoreceptor layer and decreased ganglion cell number. Also, Müller glial cells showed elevated GFAP expression compared to the aging WT retinas. Furthermore, Western blot analyses revealed significant differences between the phosphorylation state of ERK1/2 and JNK in KO mice, indicating alterations in the MAPK signaling pathway. These results support the conclusion that endogenous PACAP contributes to protection against aging of the nervous system.

Protective Role of Endogenous PACAP in Inflammation-induced Retinal Degeneration

“…In our present study, we detected dramatic changes of the retinal layers after LPS-induced inflammation in the PACAP KO groups compared to the Wt ones. These findings correlated with results of other research groups, where PACAP KO mice showed increased severe retinal abnormalities in aging or ischemia [42,43].…”

“…PACAP KO mice had significantly greater retinal damage in ischemia compared to Wt mice [42]. Furthermore, several degenerative changes were observed at an earlier age in PACAP KO mice retina [43].…”

The Impact of Aging on Brain Pituitary Adenylate Cyclase Activating Polypeptide, Pathology and Cognition in Mice and Rhesus Macaques

“…Previous studies appear to support this vicious cycle hypothesis indirectly. For example, PACAP knockout mice show accelerated retinal aging (Kovács-Valasek et al, 2017). PACAP transportation across the blood brain barrier is reduced in aged mice (Nonaka et al, 2002).…”

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

“…In other aging-related neurological disorders, such as Alzheimer's disease, pre-senile systemic amyloidosis displayed an accelerated trajectory in PACAP knockout mice, supporting the concept that PACAP may serve a neuroprotective role in age-induced degenerative processes [49], likely via sequestration of β-amyloid toxicity [50]. Moreover, PACAP-knockout mice exhibit accelerated retinal aging [51]. Such aging-mediated PACAP alteration seen in mice is also observed in aged non-human primates with cognitive impairments [52], suggesting that a deficient PACAP expression pathologically manifests as learning and memory dysfunction.…”