Aβ42 Is Essential for Parenchymal and Vascular Amyloid Deposition in Mice

Department Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
Neuron (Impact Factor: 15.05). 08/2005; 47(2):191-9. DOI: 10.1016/j.neuron.2005.06.030
Source: PubMed


Considerable circumstantial evidence suggests that Abeta42 is the initiating molecule in Alzheimer's disease (AD) pathogenesis. However, the absolute requirement for Abeta42 for amyloid deposition has never been demonstrated in vivo. We have addressed this by developing transgenic models that express Abeta1-40 or Abeta1-42 in the absence of human amyloid beta protein precursor (APP) overexpression. Mice expressing high levels of Abeta1-40 do not develop overt amyloid pathology. In contrast, mice expressing lower levels of Abeta1-42 accumulate insoluble Abeta1-42 and develop compact amyloid plaques, congophilic amyloid angiopathy (CAA), and diffuse Abeta deposits. When mice expressing Abeta1-42 are crossed with mutant APP (Tg2576) mice, there is also a massive increase in amyloid deposition. These data establish that Abeta1-42 is essential for amyloid deposition in the parenchyma and also in vessels.

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    • "Experimental studies have shown that overexpression of A 40 in transgenic mice does not result in brain A deposition, whereas expression of A 42 is known to be essential for A deposition [59] [60]. In addition , both in vitro and in vivo studies have indicated that A 40 could have an inhibitory effect on A deposition and could also possibly have neuroprotective effects [61] [62]. "
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    ABSTRACT: New therapeutic strategies in Alzheimer's disease (AD) are focused on targeting amyloid-β (Aβ) to modify the underlying cause of the disease rather than just the symptoms. The aim of this study was to investigate the long-term effects of treatment with the anti-Aβ compound phenserine on (i) cerebrospinal fluid (CSF) biomarkers for Aβ and tau pathology and (ii) brain metabolism as assessed by the regional cerebral metabolic rate for glucose (rCMRglc), using positron emission tomography. Twenty patients with mild AD were included in the study and after 12 months treatment with phenserine, CSF Aβ 40 and α- and β-secretase-cleaved soluble amyloid-β protein precursor (sAβPP) levels had significantly increased and rCMRglc had stabilized. Levels of CSF Aβ 40 and sAβPP correlated positively with rCMRglc and cognition while CSF Aβ 42 levels, the Aβ 42/40 ratio, P-tau, and T-tau correlated negatively with rCMRglc and cognition. In summary, long-term phenserine treatment resulted in increased levels of CSF Aβ 40, sAβPPα, and sAβPPβ, which positively correlated with improvements in rCMRglc and cognition. The study illustrates the value of using biomarkers in the CSF and brain for evaluation of drug effects.
    Journal of Alzheimer's disease: JAD 09/2015; 47(3):691-704. DOI:10.3233/JAD-132474 · 4.15 Impact Factor
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    • "Despite Ab 1 - 40 is in the majority in the brain of AD patients , Ab 1 - 42 is demonstrated that a major constituent of amyloid plaques . Moreover , Ab 1 - 42 aggregation plays a critical role in the initiation of plaque formation and AD pathogenesis ( McGowan et al . , 2005 ) . Ab vaccine study has showed that Ab 1 - 42 vaccines were efficient in Ab clearance and cognitive improvement ( Buckwalter et al . , 2006 ; Janus et al . , 2000 ; Morgan et al . , 2000 ) . Because Ab 1 - 42 vaccine could induce the body to produce anti - Ab antibodies , and a major proportion of the antibodies were more specific to A"
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    ABSTRACT: Anti-amyloid-β (Aβ) immunotherapy is a potential therapeutic strategy to reduce amyloid plaques and amyloid-associated pathologies in Alzheimer's disease (AD). Immune senescence with aging has also played a crucial role in AD pathogenesis and influences the effect of anti-Aβ immunotherapy. In this study, a combined treatment of Aβ1-42-bone marrow-derived dendritic cells (BMDCs) with intraperitoneal injection of splenocytes from young mice was designed as a novel immunotherapy for AD in APPswe/PSEN1de9 transgenic mice models. The results showed that the combined treatment not only elevated the level of anti-Aβ antibodies but also reduced amyloid plaques in brain and finally ameliorated deterioration of spatial learning and memory in AD mice. Additionally, the results revealed an increase of CD68 positive microglial cells in the vicinity of amyloid plaques in the mouse brain, which was responsible for the enhanced phagocytosis of Aβ plaques. In conclusion, the Aβ1-42-BMDCs plus splenocytes treatment improved the phagocytosis of microglia and prevented AD pathology more effectively. This combined immunotherapy provided a promising treatment in preventing the progression of AD in clinical studies in the near future.
    Neurobiology of Aging 07/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.06.029 · 5.01 Impact Factor
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    • "Aβ42 is formed by the sequential proteolytic cleavage of the amyloid precursor protein (APP), by β- and γ-secretases, via what is referred to as the amyloidogenic pathway and are commonly found as soluble oligomers and fibrillar plaques [3]. A considerable body of evidence suggests that soluble Aβ oligomers are the predominant neurotoxic species of Aβ, with the Aβ42 fragment being found to be particularly potent [4,5]. Aβ42 oligomers exert their toxic effects by binding to neuronal synapses, causing disruption to normal synaptic signaling, which often leads to neuronal death [6,7]. "
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    ABSTRACT: Background Alzheimer’s disease (AD) pathology occurs in part as the result of excessive production of β-amyloid (Aβ). Metabotropic glutamate receptor 5 (mGluR5) is now considered a receptor for Aβ and consequently contributes to pathogenic Aβ signaling in AD. Results Genetic deletion of mGluR5 rescues the spatial learning deficits observed in APPswe/PS1ΔE9 AD mice. Moreover, both Aβ oligomer formation and Aβ plaque number are reduced in APPswe/PS1ΔE9 mice lacking mGluR5 expression. In addition to the observed increase in Aβ oligomers and plaques in APPswe/PS1ΔE9 mice, we found that both mTOR phosphorylation and fragile X mental retardation protein (FMRP) expression were increased in these mice. Genetic deletion of mGluR5 reduced Aβ oligomers, plaques, mTOR phosphorylation and FMRP expression in APPswe/PS1ΔE9 mice. Conclusions Thus, we propose that Aβ activation of mGluR5 appears to initiate a positive feedback loop resulting in increased Aβ formation and AD pathology in APPswe/PS1ΔE9 mice via mechanism that is regulated by FMRP.
    Molecular Brain 05/2014; 7(1):40. DOI:10.1186/1756-6606-7-40 · 4.90 Impact Factor
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