Plasma Signaling Proteins in Persons at Genetic Risk for Alzheimer Disease

Ringman, John M.; Elashoff, David; Geschwind, Daniel H.; Welsh, Brian T.; Gylys, Karen H.; Lee, Cathy; Cummings, Jeffrey L.; Cole, Greg M.

doi:10.1001/archneurol.2012.277

Cited by 52 publications

(37 citation statements)

References 40 publications

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“…Although we did not observe significant differences in plaque burden between APP mice with or without apoE3 expression, it is possible that subtle but not significant changes in amyloid deposition contributed to the changes in astrogliosis. A study revealed an increased inflammatory response in young APOE4 carriers that may relate to AD risk later in life (Ringman et al, 2012). ApoE4 may have pro-inflammatory functions, less effective anti-inflammatory function, or both, which may further exacerbate AD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

ApoE4 Accelerates Early Seeding of Amyloid Pathology

Liu

Zhao

et al. 2017

Neuron

298

249

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SUMMARY Accumulation and aggregation of amyloid-β (Aβ) in the brain is an initiating step in the pathogenesis of Alzheimer’s disease (AD). The ε4 allele of apolipoprotein E (apoE) gene is the strongest genetic risk factor for late-onset AD. Although there is strong evidence showing that apoE4 enhances amyloid pathology, it is not clear what is the critical stage(s) during amyloid development apoE4 has the strongest impact. Using apoE inducible mouse models, we show that increased expression of astrocytic apoE4, but not apoE3, during the seeding stage of amyloid development enhanced amyloid deposition and neuritic dystrophy in amyloid model mice. ApoE4, but not apoE3, significantly increased brain Aβ half-life measured by in vivo microdialysis. Furthermore, apoE4 expression increased whereas apoE3 reduced amyloid-related gliosis in the mouse brains. Together, our results demonstrate that apoE4 has the greatest impact on amyloid during the seeding stage, likely by perturbing Aβ clearance and enhancing Aβ aggregation.

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Section: Discussionmentioning

confidence: 99%

ApoE4 Accelerates Early Seeding of Amyloid Pathology

Liu

Zhao

et al. 2017

Neuron

298

249

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“…There are several studies which suggest that reduced ApoE levels, observed in human ε4 carriers and in ApoE4 knock-in mouse models, might contribute to AD [16, 20]. Thus, the effect of peptide in enhancing neural levels of ApoE may be an additional mechanism by which the peptide may prevent or slow the progression of AD.…”

Section: Discussionmentioning

confidence: 99%

“…Since ApoE has a crucial role in Aβ-dependent and Aβ-independent AD pathogenic pathways, it is logical to consider strategies that regulate its expression and function. The genotype-dependent decrease in CNS ApoE levels mirrors the relative risk of developing AD, suggesting that low levels of total ApoE exhibited by ε4 carriers [16, 17] and by human ApoE4 knock-in mice [18–20], may directly contribute to the disease progression, perhaps due to reduced ApoE function in lipid metabolism, synaptic repair, and Aβ clearance. Thus, increasing the expression of ApoE irrespective of genotype might prevent or slow the progression of AD.…”

Section: Introductionmentioning

confidence: 99%

In Vivo and In Vitro Effects of an Apolipoprotein E Mimetic Peptide on Amyloid-β Pathology

Handattu

Monroe

Nayyar

et al. 2013

JAD

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Background Apolipoprotein E (ApoE) is the major apolipoprotein present in the high-density lipoprotein-like particles in the central nervous system (CNS). ApoE is involved in various protective functions in CNS including cholesterol transport, anti-inflammatory, and antioxidant effects. An ApoE peptide would be expected to exert protective effects on neuroinflammation. Objective To determine the effects of an ApoE mimetic peptide Ac-hE18A-NH2 on amyloid-β pathology. Method Using human APP/PS1ΔE9 transgenic mice and in vitro studies, we have evaluated the effect of an ApoE mimetic peptide, Ac-hE18A-NH2, on amyloid plaque deposition and inflammation. Results Administration of Ac-hE18A-NH2 to APP/PS1ΔE9 mice for 6 weeks (50 μg/mouse, 3 times a week) significantly improved cognition with a concomitant decrease in amyloid plaque deposition and reduced activated microglia and astrocytes, and increased brain ApoE levels. Oligomeric Aβ42 (oAβ42) and oxidized PAPC (ox-PAPC) inhibited secretion of ApoE in U251 cells, a human astrocyte cell line, and this effect was ameliorated in the presence of peptide Ac-hE18A-NH2. The peptide also increased Aβ42 uptake in a cell line of human macrophages. Conclusions Peptide Ac-hE18A-NH2 attenuates the effects of oxidative stress on ApoE secretion, inhibits amyloid plaque deposition, and thus could be beneficial in the treatment of Alzheimer’s disease.

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“…12 Many studies have demonstrated aberrant levels of each of these proteins in peripheral blood in AD, and have found associations between their concentrations and subsequent cognitive decline and/or imaging changes. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] We applied log 10 transformation to normalize the distribution of all ADNI1 plasma protein variables.…”

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confidence: 99%