Dataset Information

Synergistic Association between Plasma Aβ_1-42 and p-tau in Alzheimer's Disease but Not in Parkinson's Disease or Frontotemporal Dementia.

ABSTRACT: Beta-amyloid (Aβ_1-42) triggers the phosphorylation of tau protein in Alzheimer's disease (AD), but the relationship between phosphorylated tau (p-tau) and Aβ_1-42 in the blood is not elucidated. We investigated the association in individuals with AD (n = 62, including amnesic mild cognitive impairment and dementia), Parkinson's disease (n = 30), frontotemporal dementia (n = 25), and cognitively unimpaired controls (n = 41) using immunomagnetic reduction assays to measure plasma Aβ_1-42 and p-tau181 concentrations. Correlation and regression analyses were performed to examine the relation between plasma levels, demographic factors, and clinical severity. Both plasma Aβ_1-42 and p-tau concentrations were significantly higher in AD and frontotemporal dementia than in the controls and Parkinson's disease. A significant positive association was found between plasma p-tau and Aβ_1-42 in controls (r = 0.579, P < 0.001) and AD (r = 0.699, P < 0.001) but not in frontotemporal dementia or Parkinson's disease. Plasma p-tau was significantly associated with clinical severity in the AD in terms of scores of clinical dementia rating (r = 0.288, P = 0.025) and mini-mental state examination (r = -0.253, P = 0.049). Regression analysis showed that plasma Aβ_1-42 levels explain approximately 47.7% of the plasma p-tau levels in the AD after controlling age, gender, and clinical severity. While in non-AD participants, the clinical dementia rating explained about 47.5% of the plasma p-tau levels. The disease-specific association between plasma Aβ_1-42 and p-tau levels in AD implies a possible synergic effect in mechanisms involving these two pathological proteins' genesis.

SUBMITTER: Chiu MJ

PROVIDER: S-EPMC9278807 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Synergistic Association between Plasma Aβ1-42 and p-tau in Alzheimer's Disease but Not in Parkinson's Disease or Frontotemporal Dementia.

Chiu Ming-Jang MJ Yang Shieh-Yueh SY Chen Ta-Fu TF Lin Chin-Hsien CH Yang Fu-Chi FC Chen Wen-Ping WP Zetterberg Henrik H Blennow Kaj K

ACS chemical neuroscience 20210407 8

Beta-amyloid (Aβ1-42) triggers the phosphorylation of tau protein in Alzheimer's disease (AD), but the relationship between phosphorylated tau (p-tau) and Aβ1-42 in the blood is not elucidated. We investigated the association in individuals with AD (n = 62, including amnesic mild cognitive impairment and dementia), Parkinson's disease (n = 30), frontotemporal dementia (n = 25), and cognitively unimpaired controls (n = 41) using immunomagnetic red ...[more]

PMID: 33825443

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Project description:Alzheimer's disease (AD), the most common chronic neurodegenerative disorder, has complex neuropathology. The principal neuropathological hallmarks of the disease are the deposition of extracellular β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) comprised of hyperphosphorylated tau (p-tau) protein. These changes occur with neuroinflammation, a compromised blood-brain barrier (BBB) integrity, and neuronal synaptic dysfunction, all of which ultimately lead to neuronal cell loss and cognitive deficits in AD. Aβ1-42 was stereotaxically administered bilaterally into the CA1 region of the hippocampi of 18-month-old male C57BL/6 mice. This study aimed to characterize, utilizing immunohistochemistry and behavioral testing, the spatial and temporal effects of Aβ1-42 on a broad set of parameters characteristic of AD: p-tau, neuroinflammation, vascular pathology, pyramidal cell survival, and behavior. Three days after Aβ1-42 injection and before significant neuronal cell loss was detected, acute neuroinflammatory and vascular responses were observed. These responses included the up-regulation of glial fibrillary acidic protein (GFAP), cell adhesion molecule-1 (PECAM-1, also known as CD31), fibrinogen labeling, and an increased number of activated astrocytes and microglia in the CA1 region of the hippocampus. From day 7, there was significant pyramidal cell loss in the CA1 region of the hippocampus, and by 30 days, significant localized up-regulation of p-tau, GFAP, Iba-1, CD31, and alpha-smooth muscle actin (α-SMA) in the Aβ1-42-injected mice compared with controls. These molecular changes in Aβ1-42-injected mice were accompanied by cognitive deterioration, as demonstrated by long-term spatial memory impairment. This study is reporting a comprehensive examination of a complex set of parameters associated with intrahippocampal administration of Aβ1-42 in mice, their spatiotemporal interactions and combined contribution to the disease progression. We show that a single Aβ injection can reproduce aspects of the inflammatory, vascular, and p-tau induced pathology occurring in the AD human brain that lead to cognitive deficits.

Project description:Calcium ion regulation plays a crucial role in maintaining neuronal functions such as neurotransmitter release and synaptic plasticity. Copper (Cu2+ ) coordination to amyloid-β (Aβ) has accelerated Aβ1-42 aggregation that can trigger calcium dysregulation by enhancing the influx of calcium ions by extensive perturbing integrity of the membranes. Aβ1-42 aggregation, calcium dysregulation, and membrane damage are Alzheimer disease (AD) implications. To gain a detail of calcium ions' role in the full-length Aβ1-42 and Aβ1-42 -Cu2+ monomers contact, the cellular membrane before their aggregation to elucidate the neurotoxicity mechanism, we carried out 2.5 μs extensive molecular dynamics simulation (MD) to rigorous explorations of the intriguing feature of the Aβ1-42 and Aβ1-42 -Cu2+ interaction with the dimyristoylphosphatidylcholine (DMPC) bilayer in the presence of calcium ions. The outcome of the results compared to the same simulations without calcium ions. We surprisingly noted robust binding energies between the Aβ1-42 and membrane observed in simulations containing without calcium ions and is two and a half fold lesser in the simulation with calcium ions. Therefore, in the case of the absence of calcium ions, N-terminal residues of Aβ1-42 deeply penetrate from the surface to the center of the bilayer; in contrast to calcium ions presence, the N- and C-terminal residues are involved only in surface contacts through binding phosphate moieties. On the other hand, Aβ1-42 -Cu2+ actively participated in surface bilayer contacts in the absence of calcium ions. These contacts are prevented by forming a calcium bridge between Aβ1-42 -Cu2+ and the DMPC bilayer in the case of calcium ions presence. In a nutshell, Calcium ions do not allow Aβ1-42 penetration into the membranes nor contact of Aβ1-42 -Cu2+ with the membranes. These pieces of information imply that the calcium ions mediate the membrane perturbation via the monomer interactions but do not damage the membrane; they agree with the western blot experimental results of a higher concentration of calcium ions inhibit the membrane pore formation by Aβ peptides.

Dataset Information

Synergistic Association between Plasma Aβ_1-42 and p-tau in Alzheimer's Disease but Not in Parkinson's Disease or Frontotemporal Dementia.

Publications

Synergistic Association between Plasma Aβ<sub>1-42</sub> and p-tau in Alzheimer's Disease but Not in Parkinson's Disease or Frontotemporal Dementia.

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Dataset Information

Synergistic Association between Plasma Aβ1-42 and p-tau in Alzheimer's Disease but Not in Parkinson's Disease or Frontotemporal Dementia.

Publications

Synergistic Association between Plasma Aβ&lt;sub&gt;1-42&lt;/sub&gt; and p-tau in Alzheimer's Disease but Not in Parkinson's Disease or Frontotemporal Dementia.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Synergistic Association between Plasma Aβ_1-42 and p-tau in Alzheimer's Disease but Not in Parkinson's Disease or Frontotemporal Dementia.

Synergistic Association between Plasma Aβ<sub>1-42</sub> and p-tau in Alzheimer's Disease but Not in Parkinson's Disease or Frontotemporal Dementia.