Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease

Mawuenyega, Kwasi G.; Sigurdson, Wendy; Ovod, Vitaliy; Munsell, Ling Y.; Kasten, Tom; Morris, John C.; Yarasheski, Kevin E.; Bateman, Randall J.

doi:10.1126/science.1197623

Cited by 1,802 publications

(1,504 citation statements)

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“…This result indicates that there is decreased Aß clearance, without increased Aß production, in the late stage of this AD model. This phenotype is consistent with previous human studies that Aβ clearance is impaired in both early-onset and late-onset forms of AD (Mawuenyega et al 2010;Potter et al 2013). Based on this, it seems that aged APP/PS1 mice may be available for screening potential anti-AD agents targeting at Aβ clearance.…”

Section: Discussionsupporting

confidence: 91%

“…Excessive accumulation of neurotoxic Aβ peptides and subsequent formation of senile plaques in the brain parenchyma is the fundamental basis for the gradual, progressive development of AD pathology (Mawuenyega et al 2010;Holtzman et al 2011). An earlier study reported that diffuse amyloid plaques begin to appear in the hippocampus and cerebral cortex of APP/PS1 mice at 3 months old (Trinchese et al 2004).…”

Section: Discussionmentioning

confidence: 99%

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Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Huang

Nie

Cao

et al. 2016

AGE

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Transgenic APPSwe/PS1dE9 (APP/PS1) mice that overproduce amyloid beta (Aβ) are extensively used in the studies of pathogenesis and experimental therapeutics and new drug screening for Alzheimer's disease (AD). However, most of the current literature uses young or adult APP/PS1 mice. In order to provide a broader view of AD-like phenotype of this animal model, in this study, we systematically analyzed behavioral and pathological profiles of 24-month-old male APP/ PS1 mice. Aged APP/PS1 mice had reference memory deficits as well as anxiety, hyperactivity, and social interaction impairment. Consistently, there was obvious deposition of amyloid plaques in the dorsal hippocampus with decreased expression of insulin-degrading enzyme, a proteolytic enzyme responsible for degradation of intracellular Aβ. Furthermore, decreases in hippocampal volume, neuronal number and synaptophysin expression, and astrocyte atrophy were also observed in aged APP/PS1 mice. This finding suggests that aged APP/PS1 mice can well replicate cognitive and noncognitive behavioral abnormalities, hippocampal atrophy, and neuronal and astrocyte degeneration in AD patients, to enable more objective and refined preclinical evaluation of therapeutic drugs and strategies for AD treatment.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Huang

Nie

Cao

et al. 2016

AGE

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“…APOE‐ε4 is the strongest genetic risk factor for sporadic late onset AD, and markedly accelerates A β amyloid deposition in the brain and the onset age of dementia by approximately 10 years 10, 17. Recent studies have revealed that CNS‐derived A β is cleared into the CSF28 and peripheral blood,29 and that the clearance rate is decreased in late onset AD,30 and is differently regulated by age and presence of A β amyloidosis 15, 31. Association of plasma A β levels and cortical amyloid burden is also modulated by APOE isoforms 32.…”

Section: Discussionmentioning

confidence: 99%

Aging and APOE‐ε4 are determinative factors of plasma Aβ42 levels

Nakamura

Kawarabayashi

Seino

et al. 2018

Ann Clin Transl Neurol

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ObjectiveThe aim of this study was to confirm determinative factors for plasma Aβ and its association with cognitive function.MethodsFasting plasma Aβ40 and Aβ42 levels were measured by ELISA in 1019 participants in the Iwaki Health Promotion Project. The relationships between plasma Aβ and health‐related items, including physical characteristics, cognitive function tests, blood chemistry, and APOE‐ε4 genotype were analyzed.ResultsThe plasma levels of Aβ40 and Aβ42, and Aβ40/42 ratio were found to significantly increase with aging. The age‐dependent increase in Aβ42 level was significantly suppressed by APOE‐ε4. Renal function was an associated factor for the plasma Aβ40 level. The plasma Aβ42 level and Aβ40/42 ratio correlated with cognitive function.InterpretationAge and APOE‐ε4 are major determinative factors of plasma levels of Aβ42 and the Aβ40/42 ratio. These factors are critical adjustment factors for the usage of plasma Aβ as a biomarker of central nervous system amyloidosis.

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“…Mais il en existe d'autres, en particulier au niveau du site HincII-HBG1 et d'une séquence palindromique riche en AT du site HS4 du LCR (locus control region). Ces sites sont considérés comme en déséquilibre de liaison (LD) [3].…”

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Apolipoprotéine E et intégrité de la barrière hémato-encéphalique

Gosselet

2012

Med Sci (Paris)

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Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease

Abstract: Alzheimer’s disease is associated with reduced β-amyloid clearance from the brain

Cited by 1,802 publications

References 7 publications

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Aging and APOE‐ε4 are determinative factors of plasma Aβ42 levels

Apolipoprotéine E et intégrité de la barrière hémato-encéphalique

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