PACAP signaling exerts opposing effects on neuroprotection and neuroinflammation during disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic peptide with autocrine neuroprotective and paracrine anti-inflammatory properties in various models of acute neuronal damage and neurodegenerative diseases. Therefore, we examined a possible beneficial role of endogenous PACAP in the superoxide dismutase 1, SOD1(G93A), mouse model of amyotrophic lateral sclerosis (ALS), a lethal neurodegenerative disease particularly affecting somatomotor neurons. In wild-type mice, somatomotor and visceromotor neurons in brain stem and spinal cord were found to express the PACAP specific receptor PAC1, but only visceromotor neurons expressed PACAP as a potential autocrine source of regulation of these receptors. In SOD1(G93A) mice, only a small subset of the surviving somatomotor neurons showed induction of PACAP mRNA, and somatomotor neuron degeneration was unchanged in PACAP-deficient SOD1(G93A) mice. Pre-ganglionic sympathetic visceromotor neurons were found to be resistant in SOD1(G93A) mice, while pre-ganglionic parasympathetic neurons degenerated during ALS disease progression in this mouse model. PACAP-deficient SOD1(G93A) mice showed even greater pre-ganglionic parasympathetic neuron loss compared to SOD1(G93A) mice, and additional degeneration of pre-ganglionic sympathetic neurons. Thus, constitutive expression of PACAP and PAC1 may confer neuroprotection to central visceromotor neurons in SOD1(G93A) mice via autocrine pathways. Regarding the progression of neuroinflammation, the switch from amoeboid to hypertrophic microglial phenotype observed in SOD1(G93A) mice was absent in PACAP-deficient SOD1(G93A) mice. Thus, endogenous PACAP may promote microglial cytodestructive functions thought to drive ALS disease progression. This hypothesis was consistent with prolongation of life expectancy and preserved tongue motor function in PACAP-deficient SOD1(G93A) mice, compared to SOD1(G93A) mice. Given the protective role of PACAP expression in visceromotor neurons and the opposing effect on microglial function in SOD1(G93A) mice, both PACAP agonism and antagonism may be promising therapeutic tools for ALS treatment, if stage of disease progression and targeting the specific auto- and paracrine signaling pathways are carefully considered.

Characterization of the Contribution of Genetic Background and Gender to Disease Progression in the SOD1 G93A Mouse Model of Amyotrophic Lateral Sclerosis: A Meta-Analysis

“…Among mixed sex B6SJL articles, 12 report even distributions of males and females [2–13], 3 report uneven distributions without an overall bias [14–16], and the remainder report nothing concerning sex distribution. Of the mixed sex C57BL/6 articles, 5 report balanced sex distributions [17–21], 4 have unbalanced groups with a slight overall bias towards male mice among the studies [22–25], while the remainder of the articles report nothing concerning the number of males and females. To determine onset of the disease, 34 articles used deficits in the rotarod test, 8 articles used the onset of hindlimb tremors, 9 articles looked at forelimb or non-specific tremors, and 46 articles fell into the miscellaneous “General” category.…”

PACAP and PAC1R are differentially expressed in motor cortex of amyotrophic lateral sclerosis patients and support survival of iPSC‐derived motor neurons

“…In order to investigate the potential contribution of PACAP/PAC1R axis in motor neuron viability, we generated an in vitro model of human motor neurons by reprogramming PBMC through iPSC technology. Despite the beneficial role of endogenous PACAP has been already demonstrated in visceromotor neurons of SOD1(G93A) mice (Ringer et al, ), animal models often do not sufficiently reflect the more complex human disease (Morello, Spampinato, Conforti, D'Agata, & Cavallaro, ). Therefore, motor neurons‐derived from human iPSC offer a unique opportunity to obtain with a non‐invasive procedure an optimal culture of patient's specific motor neurons, opening the way to in vitro disease models suitable for drug test and/or cell therapy studies as well (Veyrat‐Durebex et al, ).…”

“…Moreover, it is known to act as a neurotransmitter and/or a neuromodulator in the peripheral and central nervous system (Jóźwiak‐Bębenista, Kowalczyk, & Nowak, ; Shioda et al, , ; Yang et al, ). Despite recent findings have revealed that PACAP is able to rescue rat motor neurons against glutamate‐induced excitotoxicity in vitro (Tomimatsu & Arakawa, ), and confers neuroprotection to central visceromotor neurons via autocrine pathways in SOD1(G93A) mice model (Ringer et al, ), the effect of PACAP in ALS still remains unknown.…”

The anti-inflammatory peptide stearyl-norleucine-VIP delays disease onset and extends survival in a rat model of inherited amyotrophic lateral sclerosis

“…These activities support the neuroprotective properties of VIP and PACAP during spinal cord injury (Waschek, 2013) and are likely mediated by the polyvalent VIP/PACAP type 1 and 2 receptors (VPAC 1 and VPAC 2 ) or the 'PACAP-preferring receptor' (PAC 1 ). The immunomodulatory role of PACAP was assigned to PAC 1 (Ohtaki et al, 2006), even though a recent study on ALS established that the preserved neuroinflammation and astrogliosis in PACAP-deficient hSOD1 G93A mice unexpectedly extends the rodent lifespan (Ringer et al, 2013). The neuropeptide SNV displays specificity and high potency for VPAC 1 and VPAC 2 , and is documented to be neuroprotective in neurodegenerative disorders (Gozes et al, 1995;Gozes et al, 1997;Offen et al, 2000).…”