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

Perényi, Helga; Szegeczki, Vince; Horváth, Gabriella; Hinnah, Barbara; Tamás, Andrea; Radák, Zsolt; Ábrahám, Dóra; Zákány, Róza; Reglődi, Dóra; Juhász, Tamás

doi:10.3389/fncel.2020.00243

Cited by 6 publications

(9 citation statements)

References 85 publications

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“…Moreover, this SpBMP-9 peptide enhanced the functions of bFGF and NGF on SH-SY5Y cell differentiation 28 . Physical activity protects the AD-induced pathological alterations in the kidneys in part via upregulation of pituitary adenylate cyclase-activating polypeptide (PACAP) and BMP4 signaling pathway 29 . One study proved that BMP4 is strongly expressed in the subgranular layer of the adult hippocampal dentate gyrus (DG) 23 .…”

Section: Discussionmentioning

confidence: 99%

BMP4 overexpression induces the upregulation of APP/Tau and memory deficits in Alzheimer’s disease

Zhang

et al. 2021

Cell Death Discov.

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Alzheimer’s disease (AD) is a chronic progressive degenerative disease of the nervous system. Its pathogenesis is complex and is related to the abnormal expression of the amyloid β (Aβ), APP, and Tau proteins. Evidence has demonstrated that bone morphogenetic protein 4 (BMP4) is highly expressed in transgenic mouse models of AD and that endogenous levels of BMP4 mainly affect hippocampal function. To determine whether BMP4 participates in AD development, transgenic mice were constructed that overexpress BMP4 under the control of the neuron-specific enolase (NSE) promoter. We also performed MTT, FACS, transfection, TUNEL, and Western blotting assays to define the role of BMP4 in cells. We found that middle-aged BMP4 transgenic mice exhibited impaired memory via the Morris water maze experiment. Moreover, their hippocampal tissues exhibited high expression levels of AD-related proteins, including APP, Aβ, PSEN-1, Tau, P-Tau (Thr181), and P-Tau (Thr231). Furthermore, in multiple cell lines, the overexpression of BMP4 increased the expression of AD-related proteins, whereas the downregulation of BMP4 demonstrated opposing effects. Consistent with these results, BMP4 modulation affected cell apoptosis via the regulation of BAX and Bcl-2 expression in cells. Our findings indicate that BMP4 overexpression might be a potential factor to induce AD.

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Section: Discussionmentioning

confidence: 99%

BMP4 overexpression induces the upregulation of APP/Tau and memory deficits in Alzheimer’s disease

Zhang

et al. 2021

Cell Death Discov.

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“…Immunohistochemistry was performed on kidney tissue samples from WT, AD mice, and TAD mice to visualize localization of Smad2, PCNA (proliferating cell nuclear antigen), and collagen type I (Col. I) [ 30 ]. Kidneys were fixed in a 4:1 mixture of absolute ethanol and 40% formaldehyde and washed in 70% ethanol.…”

Section: Methodsmentioning

confidence: 99%

“…Kidneys of WT ( n = 5), AD ( n = 5), and TAD ( n = 5) were mechanically ground and were dissolved in Trizol (Applied Biosystems, Foster City, CA, USA), after 30 min incubation on 4°C and total RNA was isolated [ 30 ]. RNA was harvested in RNase-free water and stored at –70°C.…”

Section: Methodsmentioning

confidence: 99%

“…Pellets were sonicated by pulsing burst for 30 s at 40 A (Cole-Parmer, IL, USA). Total cell lysates for western blot analyses were prepared [ 30 ]. 20 μ g protein was separated in 7.5% SDS–polyacrylamide gels for the detection of TGFβ1, TGFβR1, TGFβR2, Smad2, Smad3, ERK1/2, P-ERK1/2, p38, P-p38, JNK, PP2A, PP2B, p21, PCNA, Cleaved caspase3, MMP9, collagen type I (Col.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, it was demonstrated that long-term training of these mice had positive effects on peripheral organ dysfunctions in AD. Physical activity altered the PACAP-BMP crosstalk in AD kidneys via normalizing the expression of collagen type IV and Aβ accumulation [ 30 ]. Moreover, detailed analysis of protective function of training on Sox9 expression in AD testis has been published [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

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Physical Training Inhibits the Fibrosis Formation in Alzheimer’s Disease Kidney Influencing the TGFβ Signaling Pathways

Szegeczki

Perényi

Horváth

et al. 2021

JAD

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Background: Alzheimer’s disease (AD) is a neurodegenerative illness, with several peripheral pathological signs such as accumulation of amyloid-β (Aβ) plaques in the kidney. Alterations of transforming growth factor β (TGFβ) signaling in the kidney can induce fibrosis, thus disturbing the elimination of Aβ. Objective: A protective role of increased physical activity has been proven in AD and in kidney fibrosis, but it is not clear whether TGFβ 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 TGFβ 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 TGFβ pathways in non-trained mice, while expression levels of signal molecules of both TGFβ 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 AβPP 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 TGFβ signaling plays a role in this phenomenon.

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Same same, but different: exploring the enigmatic role of the pituitary adenylate cyclase- activating polypeptide (PACAP) in invertebrate physiology

Pirger

Gálik

Márk

et al. 2023

Preprint

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There is a long-standing debate about the presence and functionality of the pituitary adenylate cyclase-activating polypeptide (PACAP) in non-bilaterians, protostomes, and invertebrate deuterostomes. Evidence has been accumulating that homologous sequences to genes encoding PACAP peptides and their receptors in vertebrates are missing in invertebrate genomes. This is at odds, however, with the partial sequence-, immunohistochemical-, and physiological evidence in the literature. In this study, we first sequenced the neural transcriptome of the widely used invertebrate model species, the great pond snail (Lymnaea stagnalis), and then screened it for sequences homologous to the elements of the vertebrate PACAP system. Further, we performed in vitro and in vivo studies on the heart of L. stagnalis to explore the enigmatic role of vertebrate PACAP in invertebrate physiology. Our thorough screening failed to identify putative transcripts (or genes) to the vertebrate PACAP prepropeptides, active peptides, and their receptors. Despite the lack of the relevant sequences, our immunohistochemical investigations with an anti-human PAC1 receptor antibody yielded a positive signal in the neuronal elements in the heart. Although gel electrophoretic separation, followed by immunostaining, of proteins extracted from the central nervous system found a relevant band for the vertebrate PACAP-38, mass spectrometric analysis of the band did not find any corresponding peptide sequences. Similarly to the effects reported in vertebrates, 10 µM synthetic PACAP-38 significantly increased the cAMP synthesis in the homogenate of the heart and had a positive ionotropic effect on isolated heart preparations. Moreover, it modulated significantly the effects of serotonin and acetylcholine. Our findings support the idea that elements of the PACAP system are absent in mollusks and emerged after the protostome-deuterostome divergence. The physiological effects of vertebrate PACAP peptides in protostomes, no matter how similar they are to those in vertebrates, should be considered non-specific. Further studies should be aimed at investigating the cellular and molecular underpinnings including the identification of the receptors to which the vertebrate PACAP peptides may bind non-specifically.

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

Cited by 6 publications

References 85 publications

BMP4 overexpression induces the upregulation of APP/Tau and memory deficits in Alzheimer’s disease

BMP4 overexpression induces the upregulation of APP/Tau and memory deficits in Alzheimer’s disease

Physical Training Inhibits the Fibrosis Formation in Alzheimer’s Disease Kidney Influencing the TGFβ Signaling Pathways

Same same, but different: exploring the enigmatic role of the pituitary adenylate cyclase- activating polypeptide (PACAP) in invertebrate physiology

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