Aβ1–40 but not Aβ1–42 levels in cortex correlate with apolipoprotein E ϵ4 allele dosage in sporadic Alzheimer's disease

Ishii, Kazuhiro; Tamaoka, Akira; Mizusawa, Hidehiro; Shoji, Shin’ichi; Ohtake, Toshiyuki; Fraser, P.E.; Takahashi, Hitoshi; Tsuji, Shoji; Gearing, Marla; Mizutani, Toshio; Yamada, Shigeo; Kato, Masanori; George-Hyslop, Peter St; Mirra, Suzanne S.; Mori, Hiroshi

doi:10.1016/s0006-8993(96)01363-7

Cited by 79 publications

(52 citation statements)

References 21 publications

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“…The majority of A␤ fragments include A␤ 1-40 and A␤ . Although A␤ 1-42 is believed to be the protein initially deposited in diffuse plaques as the seed molecule for amyloid fibril formation, the subsequent deposition of A␤ 1-40 is more closely associated with the onset of clinical symptoms in late-onset AD (Jarret and Lansbury, 1993;Ishii et al, 1997). During the past decade, various insults have been proposed as a part of the molecular mechanisms involved in A␤-induced neurotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Tumor Necrosis Factor Death Receptor Signaling Cascade Is Required for Amyloid-β Protein-Induced Neuron Death

et al. 2004

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Tumor necrosis factor type I receptor (TNFRI), a death receptor, mediates apoptosis and plays a crucial role in the interaction between the nervous and immune systems. A direct link between death receptor activation and signal cascade-mediated neuron death in brains with neurodegenerative disorders remains inconclusive. Here, we show that amyloid-␤ protein (A␤), a major component of plaques in the Alzheimer's diseased brain, induces neuronal apoptosis through TNFRI by using primary neurons overexpressing TNFRI by viral infection or neurons from TNFRI knock-out mice. This was mediated via alteration of apoptotic protease-activating factor (Apaf-1) expression that in turn induced activation of nuclear factor B (NF-B). A␤-induced neuronal apoptosis was reduced with lower Apaf-1 expression, and little NF-B activation was found in the neurons with mutated Apaf-1 or a deletion of TNFRI compared with the cells from wild-type (WT) mice. Our studies suggest a novel neuronal response of A␤, which occurs through a TNF receptor signaling cascade and a caspase-dependent death pathway.

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Section: Introductionmentioning

confidence: 99%

Tumor Necrosis Factor Death Receptor Signaling Cascade Is Required for Amyloid-β Protein-Induced Neuron Death

et al. 2004

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“…This peptide is produced and secreted normally by cultured cells (Haass et al, 1992;Shoji et al, 1992) and is found in normal C SF (Seubert et al, 1992). Familial AD caused by genetic mutations is associated either with increased A␤ production of the more amyloidogenic peptide, A␤1-42 (Scheuner et al, 1996;Selkoe, 1997), or, as with apolipoprotein E4 (ApoE4), with increased accumulation of A␤40 (Ishii et al, 1997;Mann et al, 1997). However, the majority of AD cases is not early onset and does not appear to be linked to mutations that directly increase A␤.…”

mentioning

confidence: 99%

“…A␤40 was chosen because ApoE4 dosage, a major genetic risk factor for AD, appears to correlate positively with A␤40 accumulation (Ishii et al, 1997;Mann et al, 1997). In recognition of the possibility that the inhibition of A␤ degradation might promote toxicity, we also evaluated toxicity and glial responses.…”

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confidence: 99%

Protease Inhibitor Coinfusion with Amyloid β-Protein Results in Enhanced Deposition and Toxicity in Rat Brain

Frautschy

Horn²,

Sigel³

et al. 1998

J. Neurosci.

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Amyloid ␤-protein, A␤, is normally produced in brain and is cleared by unknown mechanisms. In Alzheimer's disease (AD), A␤ accumulates in plaque-like deposits and is implicated genetically in neurodegeneration. Here we investigate mechanisms for A␤ degradation and A␤ toxicity in vivo, focusing on the effects of A␤40, which is the peptide that accumulates in apolipoprotein E4-associated AD. Chronic intraventricular infusion of A␤40 into rat brain resulted in limited deposition and toxicity. Coinfusion of A␤40 with the cysteine protease inhibitor leupeptin resulted in increased extracellular and intracellular A␤ immunoreactivity. Analysis of gliosis and TUNEL in neuron layers of the frontal and entorhinal cortex suggested that leupeptin exacerbated A␤40 toxicity. This was supported further by the neuronal staining of cathepsin B in endosomes or lysosomes, colocalizing with intracellular A␤ immunoreactivity in pyknotic cells. Leupeptin plus A␤40 caused limited but significant neuronal phospho-tau immunostaining in the entorhinal cortex. Intriguingly, A␤40 plus leupeptin induced intracellular accumulation of the more toxic A␤, A␤42, in a small group of septal neurons. Leupeptin infusion previously has been reported to interfere with lysosomal proteolysis and to result in the accumulation of lipofuscin, dystrophic neurites, tau-and ubiquitinpositive inclusions, and structures resembling paired helical filaments. Coinfusion of A␤40 with the serine protease inhibitor aprotinin also increased diffuse extracellular deposition but reduced astrocytosis and TUNEL and was not associated with intracellular A␤ staining. Collectively, these data suggest that an age or Alzheimer's-related defect in lysosomal/endosomal function could promote A␤ deposition and DNA fragmentation in neurons and glia similar to that found in Alzheimer's disease.

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“…In some patients with sporadic AD, high plasma levels of Aβ 40 may contribute to the accumulation of Aβ 40 in preexisting plaques. 44 We found a significant correlation between APOEε4+ and high plasma Aβ 42 level which more prominent in aMCI and AD groups. The APOEε4 has been associated with reduced Aβ clearance from the brain 45 and plasma 46 and with impaired tight junction integrity.…”

Section: Discussionmentioning

confidence: 54%

Genetic risk factor APOEε4 associates with plasma amyloid beta in amnestic mild cognitive impairment and alzheimer’s disease

et al. 2016

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ABSTRAK ABSTRACTBackground: APOEε4 is a strong genetic risk factor for Alzheimer's disease (AD). AD itself has been associated with reduced Aβ clearance from the brain and plasma. Understanding the potential pathogenic link between APOEε4 and plasma Aβ might allow for earlier identification of people at risk of developing AD. The aim of this study is to find out the correlation between APOEε4 and plasma Aβ in amnestic mild cognitive impairment (aMCI) and AD patients.

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Aβ1–40 but not Aβ1–42 levels in cortex correlate with apolipoprotein E ϵ4 allele dosage in sporadic Alzheimer's disease

Cited by 79 publications

References 21 publications

Tumor Necrosis Factor Death Receptor Signaling Cascade Is Required for Amyloid-β Protein-Induced Neuron Death

Tumor Necrosis Factor Death Receptor Signaling Cascade Is Required for Amyloid-β Protein-Induced Neuron Death

Protease Inhibitor Coinfusion with Amyloid β-Protein Results in Enhanced Deposition and Toxicity in Rat Brain

Genetic risk factor APOEε4 associates with plasma amyloid beta in amnestic mild cognitive impairment and alzheimer’s disease

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