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

Abstract

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.

A multi-tissue full lifespan epigenetic clock for mice

“…We analysed the genes that were found proximal (500 kbp up- and downstream) to the identified peak SNP site. This list contains several genes that have previously been implicated in aging: Aqp1 ( Aquaporin 1 ) [ 53 ], Npy ( Neuropeptide Y ) [ 54 ], Adcyap1r1 ( Adenylate cyclase-activating polypeptide type I receptor 1 ) as a receptor for PACAP (Pituitary Adenylate Cyclase-Activating Peptide) [ 55 , 56 ]. The most notable is Npy , which encodes a hormone responsible for appetite control [ 57 ], regulation of fat metabolism [ 58 ], and plays a critical role in caloric restriction (CR) mediated lifespan extension [ 59 ].…”

Physical Activity Protects the Pathological Alterations of Alzheimer’s Disease Kidneys via the Activation of PACAP and BMP Signaling Pathways

“…One of the first signs of AD formation and manifestation is the pathological aggregation of amyloid beta (Aβ) deposits and the abnormal accumulation of tau proteins followed by inflammation (Tiraboschi et al, 2004). Amyloidogenesis is a well-controlled process in healthy tissues, but pathologic amyloid plaques can accumulate in various tissues in Alzheimer's disease (Whelly et al, 2012;Reglodi et al, 2018c). Accumulation of amyloid plaques has also been identified in peripheral organs, resulting in a systemic disorder (Morris et al, 2014;Reglodi et al, 2018c;Pomilio et al, 2020).…”

“…Amyloidogenesis is a well-controlled process in healthy tissues, but pathologic amyloid plaques can accumulate in various tissues in Alzheimer's disease (Whelly et al, 2012;Reglodi et al, 2018c). Accumulation of amyloid plaques has also been identified in peripheral organs, resulting in a systemic disorder (Morris et al, 2014;Reglodi et al, 2018c;Pomilio et al, 2020). Among others, Aβ aggregation pathologically alters pancreatic function (Kawarabayashi et al, 1996;Arbor et al, 2016;Tavares et al, 2017) and can negatively affect renal function (Kheirbakhsh et al, 2018).…”

Retinoprotective Effects of TAT-Bound Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase Activating Polypeptide

“…PACAP has a widespread occurrence in the body and a broad array of functions (Reglodi and Tamas 2016 ). Among others, PACAP influences gastrointestinal, urinary and cardiovascular functions (Heppner et al 2018 ; Parsons and May 2018 ; Reglodi et al 2018a ), plays a role in reproduction and pregnancy (Lajko et al 2018 ; Reglodi et al 2012 ; Ross et al 2018 ), has diverse behavioral and cognitive functions (Farkas et al 2017 ; Gupta et al 2018 ; Han et al 2014 ; King et al 2017 ), plays roles during both early development and aging (Fulop et al 2018 ; Reglodi et al 2018b ; Watanabe et al 2007 ), as well as influences the functions of both endocrine and exocrine glands (Bardosi et al 2016 ; Egri et al 2016 ; Prevost et al 2013 ; Sasaki et al 2017 ). VIP has also been shown to have diverse actions in addition to the originally described vasodilatory effects (Gozes 2008 ; Hill et al 2007 ; Moody and Gozes 2007 ; Vu et al 2015 ).…”