Patients with Alzheimer's disease suffer from progressive cognitive impairments and show distinct post-mortem neuropathology, including beta-amyloid plaques. Transgenic (Tg) CRND8 mice carry a mutated human amyloid precursor protein gene and show age-related increases in beta-amyloid production and plaque deposition. It was previously reported that during the early stages of plaque deposition, Tg CRND8 mice demonstrated Morris maze impairments. However, it is unknown if Tg mice would be impaired at an earlier age prior to plaque deposition or more impaired at a later age with more extensive plaque deposition. In the current study, we describe Tg CRND8 age-progressing beta-amyloid neuropathology and cognitive abilities in greater detail. At all ages, Tg mice showed normal short-term memory in the Y-maze. Pre-plaque Tg and age-matched Non-Tg mice did not differ in learning the spatial Morris water maze. However, both early and late plaque Tg mice showed impairments during acquisition. In addition, although early plaque Tg mice performed well in the probe trial, late plaque Tg mice demonstrated impaired probe trial performance. Therefore compared to their Non-Tg littermates, Tg CRND8 mice demonstrate cognitive impairments that progressed with age and seemed to coincide with the onset of beta-amyloid plaque deposition.
"To recapitulate clinical relevance in a mouse AD model (CRND8), we investigated Aβ plaques in a transgenic mouse AD model, which carries double mutations in 695 amino acid isoform of the amyloid precursor protein (APP)25. This is a relatively aggressive AD model and transgenic mice begin to develop obvious memory impairment at the age around week 15 after birth. "
[Show abstract][Hide abstract] ABSTRACT: The functional impact of amyloid peptides (Aβs) on the vascular system is less understood despite these pathologic peptides are substantially deposited in the brain vasculature of Alzheimer's patients. Here we show substantial accumulation of Aβs 40 and 42 in the brain arterioles of Alzheimer's patients and of transgenic Alzheimer's mice. Purified Aβs 1-40 and 1-42 exhibited vascular regression activity in the in vivo animal models and vessel density was reversely correlated with numbers and sizes of amyloid plaques in human patients. A significant high number of vascular cells underwent cellular apoptosis in the brain vasculature of Alzheimer's patients. VEGF significantly prevented Aβ-induced endothelial apoptosis in vitro. Neuronal expression of VEGF in transgenic mice restored memory behavior of Alzheimer's. These findings provide conceptual implication of improvement of vascular functions as a novel therapeutic approach for the treatment of Alzheimer's disease.
"The transgenic (Tg) CRND8 male and female (counterbalanced across groups) mice (carrying the Swedish and Indiana familial Alzheimer's disease APP mutations under the control of the Syrian hamster prion protein ) used in these studies were bred at Merck Research Laboratories in Kenilworth, NJ, or Taconic in Germantown, NY, as described previously . Before dosing began and for the duration of the study, mice were singly housed with a plastic igloo and nesting material. "
[Show abstract][Hide abstract] ABSTRACT: Substantial evidence implicates β-amyloid (Aβ) peptides in the etiology of Alzheimer's disease (AD). Aβ is produced by the proteolytic cleavage of the amyloid precursor protein by β- and γ-secretase suggesting that γ-secretase inhibition may provide therapeutic benefit for AD. Although many γ-secretase inhibitors have been shown to be potent at lowering Aβ, some have also been shown to have side effects following repeated administration. All of these side effects can be attributed to altered Notch signaling, another γ-secretase substrate. Here we describe the in vivo characterization of the novel γ-secretase inhibitor SCH 697466 in rodents. Although SCH 697466 was effective at lowering Aβ, Notch-related side effects in the intestine and thymus were observed following subchronic administration at doses that provided sustained and complete lowering of Aβ. However, additional studies revealed that both partial but sustained lowering of Aβand complete but less sustained lowering of Aβ were successful approaches for managing Notch-related side effects. Further, changes in several Notch-related biomarkers paralleled the side effect observations. Taken together, these studies demonstrated that, by carefully varying the extent and duration of Aβ lowering by γ-secretase inhibitors, it is possible to obtain robust and sustained lowering of Aβ without evidence of Notch-related side effects.
International Journal of Alzheimer's Disease 03/2013; 2013(5054):823528. DOI:10.1155/2013/823528
"Zhang et al. studied APP and PS1 mutants alone and together and observed diminished neurogenesis only in the double-mutant mice (Zhang et al., 2007). The double transgenic (Tg) CRND8 mice (overexpressing the Swedish and Indiana mutations of the human amyloid precursor protein) show age-related increases in behavioural deficits and severity of the pathology (Bellucci et al., 2006; Hyde et al., 2005; Cameron and McKay, 2001). CRND8 mice aged 2 and 6 months were used to examine the in vivo effects of 5 weeks of lithium treatment. "
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) is an age-related, progressive and irreversible neurodegenerative disease that results in the loss of selected neurons throughout the basal forebrain, amygdala, hippocampus, and cortical area as well as progressive deficits of cognition and memory. The subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) is one of the regions where adult neurogenesis occurs in mammals, including humans and non-human primates. The new granule cells, which are the primary excitatory neurons in the DG, contribute to the processes of learning and memory. The changes in neurogenesis observed during the initial stages and progression of AD suggest that the modulation of the new production of neurons at neurogenic sites may exert profound effects on hippocampal function. Bone morphogenetic protein-4 (BMP4) and its antagonist Noggin contribute to the modulation of neurogenesis in the adult hippocampus, thereby affecting hippocampal function. This review focuses on the role of BMP4 and Noggin in the control of the stem and precursor cells in the adult hippocampus during AD and their potential as a possible therapeutic strategy for AD sufferers. It is helpful to extend the understanding of the control of stem cells in the normal and diseased hippocampus.
Ageing research reviews 06/2012; 12(1):157-164. DOI:10.1016/j.arr.2012.05.002 · 4.94 Impact Factor
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