Presence of Systemic Amyloidosis in Mice with Partial Deficiency in Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in Aging

Jason Sparks,Gabriella Kiss,Adel Jungling,Daniel Pham,Andrea Tamas,Attila Miseta,Orsolya Hoffmann,Laszlo Hiripi,Sebastian Bardosi,Dora Reglodi

doi:10.3390/app11167373

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide with widespread expression and general cytoprotective effects, is also involved in aging. Previously, we observed accelerated systemic senile amyloidosis in PACAP knockout (KO) mice. As mice partially lacking PACAP (heterozygous-HZ) show variable symptoms, here we investigated whether HZ mice have accelerated aging, completed with observations in PAC1 receptor KO mice. As we have limited data on qualitative or quantitative changes in the blood of PACAP-deficient mice, we investigated whether these changes could be in the background of the amyloidosis. Routine histological staining was used to examine amyloid deposits, rated on a severity scale 0–3. Blood was collected from PACAP wild type/HZ mice for complete blood analysis. In contrast to receptor KO mice showing no amyloidosis, histopathological analysis revealed severe deposits in PACAP HZ mice, with kidney, spleen, skin, and intestines being most affected. Increased cholesterol, lipoprotein levels, and differences in several blood count parameters were found in HZ mice. In summary, amyloidosis also develops in partial absence of PACAP, in contrast to the lack of its PAC1 receptor. In addition to the earlier identified inflammatory and degenerative disturbances, the alteration in lipid metabolism and bone marrow activity can also be additional factors leading to systemic degenerative processes.

Highlights

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with 38(PACAP38) or 27 (PACAP27) amino acid residues [1]
As mice partially lacking PACAP show variable symptoms, here we investigated whether HZ mice have accelerated aging, completed with observations in PAC1 receptor KO mice
We have found that mice lacking endogenous PACAP display an early onset systemic amyloidosis present in most organs [28]

Summary

Introduction

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with 38(PACAP38) or 27 (PACAP27) amino acid residues [1]. In addition to the receptorial mechanisms of action, PACAP is able to traverse biological barriers and act directly intracellularly, and it transactivates other receptors [1,2]. The eight splice variants of the PAC1 receptor activate different signal transduction pathways. The splice variants of the receptor, the different signaling pathways, and the other routes of action are responsible for the very diverse actions of the peptide. PACAP acts as a growth factor and influences the development of the nervous system as well as peripheral organs. These effects include actions on neuronal mitosis, migration, myelination, and tissue differentiation [13,14,15,16,17]. PACAP plays a role in haemopoetic stem cell proliferation [18], and skeletal and immune development [19,20]

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