TGF-β1 is increased in a transgenic mouse model of familial Alzheimer's disease and causes neuronal apoptosis

Salins, Pradeep; He, Yang; Olson, Kelly L.; Glazner, Gordon W.; Kashour, Tarek; Amara, Francis M.

doi:10.1016/j.neulet.2007.10.025

Cited by 38 publications

(33 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alternatively, TGF-1 signaling can lead to neuronal apoptosis in AD due to A toxicity. In our study, we showed that Smad7 interaction with -catenin, under A 1-42 toxicity leads to apoptosis [83]. A recent study has shown that statins promote TGF-1 signaling by activating Smad2 and Smad3, leading to cell survival.…”

Section: Anti-apoptotic Signaling Pathways Of Statins In Adsupporting

confidence: 55%

Neuroprotective Role of Statins in Alzheimer`s Disease: Anti-Apoptotic Signaling~!2009-02-06~!2010-04-04~!2010-06-22~!

Hunt¹,

Salins²,

Anderson³

et al. 2010

TONEURJ

View full text Add to dashboard Cite

Alzheimer's disease (AD), a severe form of senile dementia is a neurodegenerative disorder. One of the most well characterized hallmarks of AD are extra-neuronal aggregates of amyloid-beta peptide (A ), known as amyloid plaques. Recent epidemiological studies suggest a link between statin intake, and a lowered incidence of AD. Statins are 3-hydroxy-3-methylglutaryl co-enzyme reductase (HMG) inhibitors, which are one of the most commonly prescribed drug groups used to lower serum cholesterol levels in patients with heart disease. Some of the pleiotropic effects of statins which are gaining attention are its ability to reduce A production and deposition, inhibit caspase-3 mediated apoptosis, and demonstrate anti-inflammatory properties by reducing interleukin-6 (IL-6) levels. The molecular mechanisms responsible for the pleiotropic effects of statins in promoting neuronal survival are not fully understood. Our own research has shown that statins promote anti-apoptotic responses against A -neurotoxicity through -catenin-TCF/LEF signaling however, other anti-apoptotic statin mediated signaling pathways may also be involved. This review will describe AD pathogenesis, A production, and the role of statins in mitigating these effects.

show abstract

Section: Anti-apoptotic Signaling Pathways Of Statins In Adsupporting

confidence: 55%

Neuroprotective Role of Statins in Alzheimer`s Disease: Anti-Apoptotic Signaling~!2009-02-06~!2010-04-04~!2010-06-22~!

Hunt¹,

Salins²,

Anderson³

et al. 2010

TONEURJ

View full text Add to dashboard Cite

show abstract

“…48,58,59 However, evidence for a TGF-␤1 neurodegenerative action has also been presented. 17,60 Further, neuronal malfunction was apparent in A/T mice, in the form of impaired stimulusevoked cerebral glucose uptake and eventual spatial memory decline. Moreover, given the detrimental cerebrovascular effects of TGF-␤1, 15,19,24,29,61 alternative neuroprotective approaches should be considered.…”

Section: Contribution Of A␤ Versus Tgf-␤1 To the Neuronal And Cognitimentioning

confidence: 99%

Transgenic Mice Overexpressing APP and Transforming Growth Factor-β1 Feature Cognitive and Vascular Hallmarks of Alzheimer's Disease

Ongali

Nicolakakis

Lecrux

et al. 2010

The American Journal of Pathology

View full text Add to dashboard Cite

High brain levels of amyloid-␤ (A␤) and transforming growth factor-␤1 (TGF-␤1) have been implicated in the cognitive and cerebrovascular alterations of Alzheimer's disease (AD). We sought to investigate the impact of combined increases in A␤ and TGF-␤1 on cerebrovascular, neuronal, and mnemonic function using transgenic mice overproducing these peptides (A/T mice). In particular, we measured cerebrovascular reactivity, evoked cerebral blood flow and glucose uptake during brain activation, cholinergic status, and spatial memory, along with cerebrovascular fibrosis, amyloidosis, and astrogliosis, and their evolution with age. An assessment of perfusion and metabolic responses was considered timely, given ongoing efforts for their validation as AD biomarkers. Relative to wild-type littermates, A/T mice displayed an early progressive decline in cerebrovascular dilatory ability, preserved contractility, and reduction in constitutive nitric oxide synthesis that establishes resting vessel tone. Altered levels of vasodilator-synthesizing enzymes and fibrotic proteins, resistance to antioxidant treatment, and unchanged levels of the antioxidant enzyme, superoxide dismutase-2, accompanied these impairments. A/T mice featured deficient neurovascular and neurometabolic coupling to whisker stimulation, cholinergic denervation, cerebral and cerebrovascular A␤ deposition, astrocyte activation , and impaired Morris water maze performance , which gained severity with age. The combined A␤-and TGF-␤1-driven pathology recapitulates salient cerebrovascular, neuronal, and cognitive AD landmarks and yields a versatile model toward highly anticipated diagnostic and therapeutic tools for patients featuring A␤ and TGF-␤1 increments.

show abstract

“…Previous studies have shown that the TGF-␤ system is affected in AD, with the most consistent findings being increased levels of TGF-␤ 1 and decreased levels of the T ␤ RII [23,24] . This contrasts with the present findings that apoE4 mainly affects TGF-␤ 3 ( fig.…”

Section: Resultsmentioning

confidence: 77%

The Effects of Apolipoproteins E3 and E4 on the Transforming Growth Factor-β System in Targeted Replacement Mice

2012

View full text Add to dashboard Cite

Background: This study examined the possibility that apolipoprotein E4 (apoE4), the most prevalent genetic risk factor of Alzheimer’s disease, interacts isoform specifically with the transforming growth factor (TGF)-β system. Methods: This was pursued by measurements of the effects of apoE3 and apoE4 on the levels of TGF-β ligands and on activation of the Smad system in brains of human apoE targeted replacement mice, utilizing Western blot. Results: The study revealed that apoE4 reduces, isoform specifically, the levels of TGF-β₁, TGF-β₂ and TGF-β₃ in the septum and of TGF-β₃ in the hippocampus. In contrast, the levels and extent of phosphorylation of Smad1, 5 and 8 as well as of Smad2 and Smad3 in these brain areas were not affected by apoE4, suggesting that the apoE4-driven effects on the TGF-β system may be mediated via the Smad-independent non-canonical pathway. Conclusion: The possible role of the TGF-β system in mediating the pathological effects of apoE4 is discussed.

show abstract

TGF-β1 is increased in a transgenic mouse model of familial Alzheimer's disease and causes neuronal apoptosis

Cited by 38 publications

References 22 publications

Neuroprotective Role of Statins in Alzheimer`s Disease: Anti-Apoptotic Signaling~!2009-02-06~!2010-04-04~!2010-06-22~!

Neuroprotective Role of Statins in Alzheimer`s Disease: Anti-Apoptotic Signaling~!2009-02-06~!2010-04-04~!2010-06-22~!

Transgenic Mice Overexpressing APP and Transforming Growth Factor-β1 Feature Cognitive and Vascular Hallmarks of Alzheimer's Disease

The Effects of Apolipoproteins E3 and E4 on the Transforming Growth Factor-β System in Targeted Replacement Mice

Contact Info

Product

Resources

About