Alzheimer's Disease Mouse as a Model of Testis Degeneration.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with protective functions in the central nervous system and various peripheral organs. PACAP has the highest expression level in the testes, among the peripheral organs, and has a positive regulative role in spermatogenesis and in sperm motility. In the present study, we explored testicular degenerative alterations in a mouse model of Alzheimer's disease (AD) (B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J) and demonstrated changes in PACAP-regulated signaling pathways. In addition, the effects of increased physical activity of AD (trained AD (TAD)) mice on testis were also followed. Reduced cell number and decreased thickness of basement membrane were detected in AD samples. These changes were compensated by physical activity. Expression of PACAP receptors and canonical signaling elements such as PKA, P-PKA, PP2A significantly decreased in AD mice, and altered Sox transcription factor expression was also detected. Via this signaling mechanism, physical activity compensated the negative effects of AD on the expression of type IV collagen. Our findings suggest that the testes of AD mice can be a good model of testis degeneration. Moreover, it can be an appropriate organ to follow the effects of various interventions such as physical activity on tissue regeneration and signaling alterations.

Physical Training Inhibits the Fibrosis Formation in Alzheimer's Disease Kidney Influencing the TGFß Signaling Pathways.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative illness, with several peripheral pathological signs such as accumulation of amyloid-ß (Aß) plaques in the kidney. Alterations of transforming growth factor ß (TGFß) signaling in the kidney can induce fibrosis, thus disturbing the elimination of Aß. OBJECTIVE: A protective role of increased physical activity has been proven in AD and in kidney fibrosis, but it is not clear whether TGFß signalization is involved in this effect. METHODS: The effects of long-term training on fibrosis were investigated in the kidneys of mice representing a model of AD (B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J) by comparing wild type and AD organs. Alterations of canonical and non-canonical TGFß signaling pathways were followed with PCR, western blot, and immunohistochemistry. RESULTS: Accumulation of collagen type I and interstitial fibrosis were reduced in kidneys of AD mice after long-term training. AD induced the activation of canonical and non-canonical TGFß pathways in non-trained mice, while expression levels of signal molecules of both TGFß pathways became normalized in trained AD mice. Decreased amounts of phosphoproteins with molecular weight corresponding to that of tau and the cleaved C-terminal of AßPP were detected upon exercising, along with a significant increase of PP2A catalytic subunit expression. CONCLUSION: Our data suggest that physical training has beneficial effects on fibrosis formation in kidneys of AD mice and TGFß signaling plays a role in this phenomenon.

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

Alzheimer's disease (AD) is a neurodegenerative disorder with typical amyloid beta (Aß) aggregations. Elimination of the Aß precursors via the kidneys makes the organ a potential factor in the systemic degeneration leading to AD. Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts neuroprotective effects in AD and plays a protective role in kidney pathologies. Increased physical activity is preventive of the formation of AD, but its detailed mechanism and possible connections with PACAP have not been clarified. In the kidneys of AD mice, the effects of physical activity were investigated by comparing wild-type and AD organs. Aß plaque formation was reduced in AD kidneys after increased training (TAD). Mechanotransduction elevated PACAP receptor expression in TAD mice and normalized the protein kinase A (PKA)-mediated pathways. BMP4/BMPR1 elevation activated Smad1 expression and normalized collagen type IV in TAD animals. In conclusion, our data suggest that elevated physical activity can prevent the AD-induced pathological changes in the kidneys via, at least in part, the activation of PACAP-BMP signaling crosstalk.

Age-related alterations of articular cartilage in pituitary adenylate cyclase-activating polypeptide (PACAP) gene-deficient mice.

Pituitary adenylate cyclase activating polypeptide (PACAP) is an evolutionarly conserved neuropeptide which is produced by various neuronal and non-neuronal cells, including cartilage and bone cells. PACAP has trophic functions in tissue development, and it also plays a role in cellular and tissue aging. PACAP takes part in the regulation of chondrogenesis, which prevents insufficient cartilage formation caused by oxidative and mechanical stress. PACAP knockout (KO) mice have been shown to display early aging signs affecting several organs. In the present work, we investigated articular cartilage of knee joints in young and aged wild-type (WT) and PACAP KO mice. A significant increase in the thickness of articular cartilage was detected in aged PACAP gene-deficient mice. Amongst PACAP receptors, dominantly PAC1 receptor was expressed in WT knee joints and a remarkable decrease was found in aged PACAP KO mice. Expression of PKA-regulated transcription factors, Sox5, Sox9 and CREB, decreased both in young and aged gene deficient mice, while Sox6, collagen type II and aggrecan expressions were elevated in young but were reduced in aged PACAP KO animals. Increased expression of hyaluronan (HA) synthases and HA-binding proteins was detected parallel with an elevated presence of HA in aged PACAP KO mice. Expression of bone related collagens (I and X) was augmented in young and aged animals. These results suggest that loss of PACAP signaling results in dysregulation of cartilage matrix composition and may transform articular cartilage in a way that it becomes more prone to degenerate.