Enhanced Proteolysis of β-Amyloid in APP Transgenic Mice Prevents Plaque Formation, Secondary Pathology, and Premature Death

Leissring, Malcolm A.; Farris, Wesley; Chang, Alice Y.W.; Walsh, Dominic M.; Wu, Xining; Sun, Xiaoyan; Frosch, Matthew P.; Selkoe, Dennis J.

doi:10.1016/s0896-6273(03)00787-6

Cited by 651 publications

(533 citation statements)

References 38 publications

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“…197,198 An age-related reduction in neprilysin expression has also been reported. 199 Recently, a number of studies have suggested that environmental enrichment and physical activity may reduce Ab load and lower the risk of developing AD in animal models 200,201 and epidemiological studies, 202,203 respectively.…”

Section: Ab-degrading Enzymesmentioning

confidence: 89%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-b (Ab) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Ab is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Ab leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Ab are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Ab clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Ab ELISAs are discussed, as are the more promising results of Ab imaging by positron emission tomography. Current knowledge of Ab-binding proteins and Ab-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Ab remains an attractive therapeutic strategy, and improved understanding of Ab clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.

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Section: Ab-degrading Enzymesmentioning

confidence: 89%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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“…Overexpression of NEP or IDE in neurons of transgenic mice showed reduction in the levels of soluble Ab, prevention of amyloid plaque formation, and extension of lifespan (Leissring et al, 2003). We determined whether social isolation affected NEP and IDE by immunoblotting the expression of IDE and NEP with anti-IDE and anti-NEP antibodies in the APP/PS1 mice.…”

Section: Social Isolation Increases Hippocampal Levels Of Ab 40 and Amentioning

confidence: 99%

The Involvement of Cdk5 Activator p35 in Social Isolation-Triggered Onset of Early Alzheimer’s Disease-Related Cognitive Deficit in the Transgenic Mice

Hsiao

Chen

et al. 2011

Neuropsychopharmacol

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Epidemiological studies indicate that isolated persons have increased risk of developing Alzheimer's disease (AD). This study investigated the cellular mechanisms of how social isolation influenced amyloid b peptide (Ab) accumulation and affected the severity of AD-associated cognitive decline in a mouse model of AD. Amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (APP/PS1) mice were placed either in isolation or in group from postnatal day 28 and tested for cognitive performance at the age of 3 months with fear-conditioning paradigms. We found that social isolation accelerated impairment of contextual fear memory in the APP/PS1 mice. The magnitude of long-term potentiation in the hippocampal CA1 neurons was significantly lower in the isolated APP/PS1 mice compared with group APP/PS1 and wild-type mice. Hippocampal level of Ab was significantly elevated in the isolated APP/PS1 mice, which was accompanied by an increased calpain activity and p25/p35 ratio. In addition, surface expression of GluR1 subunit of AMPA receptor was decreased by social isolation. The association of p35, and a-CaMKII was significantly less in the isolated APP/PS1 mice indicating that their interaction was impaired. These results suggest that social isolation exacerbates memory deficit by increasing Ab level, leading to the increased calpain activity, conversion of p35 to p25 and decrease in association of p35, a-CaMKII, and GluR1, resulting in the endocytosis of AMPA receptors.

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“…These findings might be clinically relevant given the fact that neprilysin expression in the brain decreases during aging and in the early stages of AD progression (Yasojima et al, 2001;Iwata et al, 2002), whereas elevated neprilysin activity reduces the accumulation of both soluble and fibrillar A in APP transgenic mice (Leissring et al, 2003;Iwata et al, 2004).…”

Section: Page 11 Of 31mentioning

confidence: 89%

Somatostatin and Alzheimer's disease

Burgos‐Ramos

Hervás-Aguilar

Aguado-Llera

et al. 2008

Molecular and Cellular Endocrinology

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Enhanced Proteolysis of β-Amyloid in APP Transgenic Mice Prevents Plaque Formation, Secondary Pathology, and Premature Death

Cited by 651 publications

References 38 publications

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

The Involvement of Cdk5 Activator p35 in Social Isolation-Triggered Onset of Early Alzheimer’s Disease-Related Cognitive Deficit in the Transgenic Mice

Somatostatin and Alzheimer's disease

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