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At least 685 records · Page 38Linked to original sources
PubMed2002

Aluminum modulates brain amyloidosis through oxidative stress in APP transgenic mice.

Epidemiological studies have implicated aluminum (Al) exposure in the pathogenesis of Alzheimer's disease (AD); however, other studies have failed to confirm these results. Oxidative stress is a feature of AD, and Al can exacerbate oxidative events. This biological property has been suggested as a possible mechanism by which this metal could influence the onset and/or evolution of the disease. To test this hypothesis, we fed transgenic mice that over express human amyloid precursor protein (Tg2576) with a diet enriched in Al and measured isoprostane levels, sensitive and specific markers of in vivo oxidative stress, as well as amyloid b peptide formation and deposition. Here, we show an increase in brain isoprostane levels that correlated with increased amyloid b levels and accelerated plaque deposition in Tg2576 mice but not in wild-type (WT) littermates fed with high dietary Al. Significantly, these in vivo effects of Al were reversed by vitamin E, as judged by a reduction of isoprostane production, amyloid b levels, and plaque deposition. These results indicate that dietary Al can modulate in vivo AD-like amyloidosis in Tg2576 by increasing brain oxidative stress.

Administration, Oral↗
PubMed2006

Transgenic expression of beta-APP in fast-twitch skeletal muscle leads to calcium dyshomeostasis and IBM-like pathology.

Intracellular deposition of the beta-amyloid (Abeta) peptide is an increasingly recognized pathological hallmark associated with neurodegeneration and muscle wasting in Alzheimer's disease (AD) and inclusion body myositis (IBM), respectively. Previous reports have implicated dysregulation of beta-amyloid precursor protein (betaAPP) expression in IBM. Accumulation of full-length betaAPP, its various proteolytic derivatives including Abeta, and phospho-tau into vacuolated inclusions is an early pathogenic event. We previously reported on a statistical tendency favoring fast twitch fiber involvement in IBM, reminiscent of the tissue specific patterns of misfolded protein deposition seen in neurodegenerative diseases. To test this principle, we generated an animal model in which human wild-type (WT) betaAPP expression was limited to postnatal type II skeletal muscle. Hemizygous transgenic mice harboring increased levels of holo betaAPP751 and Abeta in skeletal muscle fibers became significantly weaker with age compared with nontransgenic littermates and exhibited typical myopathic features. A subpopulation of dissociated muscle fibers from transgenic mice exhibited a 2-fold increase in resting calcium and membrane depolarization compared with nontransgenic littermates. Taken together, these data indicate that overexpression of human betaAPP in fast twitch skeletal muscle of transgenic mice is sufficient for the development of some features characteristic of IBM, including abnormal tau histochemistry. The increase in resting calcium and depolarization are novel findings, suggesting both a mechanism for the weakness and an avenue for therapeutic intervention in IBM.

Amyloid beta-Protein Precursor↗
PubMedDate not supplied

Search strategies used by APP transgenic mice during navigation in the Morris water maze.

TgCRND8 mice represent a transgenic mouse model of Alzheimer's disease, with onset of cognitive impairment and increasing amyloid-beta plaques in their brains at 12 weeks of age. In this study, the spatial memory in 25- to 30-week-old TgCRND8 mice was analyzed in two reference and one working memory Morris water maze (MWM) tests. In reference memory tests, the mice were trained to escape to a hidden platform, which in one version of the test was marked by a visual cue. In the working memory test, the hidden platform was moved daily to different locations. The TgCRND8 mice were impaired in reference memory when trained in a hidden platform test. However, the mice developed spatial memory comparable to non-Tg littermates in a cued reference memory test. The mice showed also an impairment in spatial working memory. Analysis of search paths revealed that in contrast to non-Tg littermates, TgCRND8 mice did not use spatial strategies during their navigation. Instead, they learned to locate an escape platform using a nonspatial, chaining strategy. The study showed that (1) the impairment in the reference memory of TgCRND8 mice was reduced when a hidden platform was cued, and that (2) both working and reference memory systems of TgCRND8 mice, but not (3) the plasticity of choice between search strategies, are compromised by the transgene-induced pathology.

Adaptation, Physiological↗
PubMed2004

Accelerated accumulation of N- and C-terminal beta APP fragments and delayed recovery of microtubule-associated protein 1B expression following stroke in aged rats.

The age-related decline in plasticity of the brain may be one factor underlying poor functional recovery after stroke. In the present work we tested the hypothesis that the attenuation of neural plasticity in old age could be the result of an altered temporal relationship between factors promoting brain plasticity [microtubule-associated protein 1B (MAP1B)] and neurotoxic factors such as C-terminal betaAPP. Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3- and 20-month-old male Sprague-Dawley rats. The functional outcome was assessed in neurobehavioral tests at 3, 7, 14 and 28 days after surgery. At the indicated timepoints, brains were removed and immunostained for C- and N-terminal betaAPP and MAP1B. At 2 weeks poststroke, we found an age-related increase in the amount of the C-terminal fragment of betaAPP in the peri-infarcted area and the infarct core as well as an early, vigorous incorporation of N-terminal betaAPP into the developing astroglial scar. The recovery of the plasticity-associated protein MAP1B following stroke was delayed in both age groups and became prominent between days 14 and 28. As aged rats showed diminished functional recovery compared with young rats, these results suggest that the accumulation of C-terminal betaAPP, together with the early incorporation of N-terminal betaAPP into the glial scar, may over-ride the beneficial role of plasticity factors such as MAP1B.

Aging↗
PubMed1979

Synthesis and biological effect of the C-terminal pentapeptide amide of avian pancreatic hormone III (APP).

Model building studies and analogies drawn from peptides of similar biological activity have indicated that the C-terminus of avian pancreatic hormone III may possess significant biological information. To test this hypothesis, the C-terminal pentapeptide amide sequence has been synthesized by the Merrifield method. The synthesis, purification and characterization of this compound are reported here in detail. In vivo studies indicate that this synthetic segment possesses none of the secretogogic activity of the parent hormone; rather, it reduces "gastric" secretion levels even in the presence of the intact hormone.

Amides↗
PubMed2005

mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer's disease.

In Alzheimer's disease, neuropathological hallmarks include the accumulation of beta-amyloid peptides (Abeta) in senile plaques, phosphorylated tau in neurofibrillary tangles and neuronal death. Abeta is the major aetiological agent according to the amyloid cascade hypothesis. Translational control includes phosphorylation of the kinases mammalian target of rapamycin (mTOR) and p70S6k which modulate cell growth, proliferation and autophagy. It is mainly part of an anti-apoptotic cellular signalling. In this study, we analysed modifications of mTOR/p70S6k signalling in cellular and transgenic models of Alzheimer's disease, as well as in lymphocytes of patients and control individuals. Abeta 1-42 produced a rapid and persistent down-regulation of mTOR/p70S6k phosphorylation in murine neuroblastoma cells associated with caspase 3 activation. Using western blottings, we found that phosphorylated forms of mTOR and p70S6k are decreased in the cortex but not in the cerebellum (devoid of plaques) of double APP/PS1 transgenic mice compared with control mice. These results were confirmed by immunohistochemical methods. Finally, the expression of phosphorylated p70S6k was significantly reduced in lymphocytes of Alzheimer's patients, and levels of phosphorylated p70S6k were statistically correlated with Mini Mental Status Examination (MMSE) scores. Taken together, these findings demonstrate that the mainly anti-apoptotic mTOR/p70S6k signalling is altered in cellular and transgenic models of Alzheimer's disease and in peripheral cells of patients, and could contribute to the pathogenesis of the disease.

Aged↗
PubMed2000

Synaptic structure and function in transgenic APP mice.

Efforts using transgenic mice are being made to understand the molecular and structural basis for dementia in Alzheimer's disease. Transgenic mice 12 to 18 months of age with amyloid plaques and impaired cognition show no neuronal or synaptic loss in the CA1 hippocampal subfield. Electrophysiological studies may yield new insights.

Alzheimer Disease↗