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Amyloid-beta uptake by blood monocytes is reduced with ageing and Alzheimer's disease.

ABSTRACT: Deficits in the clearance of amyloid ?-protein (A?) play a pivotal role in the pathogenesis of sporadic Alzheimer's disease (AD). The roles of blood monocytes in the development of AD remain unclear. In this study, we sought to investigate the alterations in the A? phagocytosis function of peripheral monocytes during ageing and in AD patients. A total of 104 cognitively normal participants aged 22-89 years, 24 AD patients, 25 age- and sex-matched cognitively normal (CN) subjects, 15 Parkinson's disease patients (PD), and 15 age- and sex-matched CN subjects were recruited. The A? uptake by blood monocytes was measured and its alteration during ageing and in AD patients were investigated. A?_1-42 uptake by monocytes decreased during ageing and further decreased in AD but not in PD patients. A?_1-42 uptake by monocytes was associated with A?_1-42 levels in the blood. Among the A? uptake-related receptors and enzymes, the expression of Toll-like receptor 2 (TLR2) was reduced in monocytes from AD patients. Our findings suggest that monocytes regulate the blood levels of A? and might be involved in the development of AD. The recovery of the A? uptake function by blood monocytes represents a potential therapeutic strategy for AD.

SUBMITTER: Chen SH

PROVIDER: S-EPMC7722845 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Amyloid-beta uptake by blood monocytes is reduced with ageing and Alzheimer's disease.

Chen Si-Han SH Tian Ding-Yuan DY Shen Ying-Ying YY Cheng Yuan Y Fan Dong-Yu DY Sun Hao-Lun HL He Chen-Yang CY Sun Pu-Yang PY Bu Xian-Le XL Zeng Fan F Liu Juan J Deng Juan J Xu Zhi-Qiang ZQ Chen Yang Y Wang Yan-Jiang YJ

Translational psychiatry 20201208 1

Deficits in the clearance of amyloid β-protein (Aβ) play a pivotal role in the pathogenesis of sporadic Alzheimer's disease (AD). The roles of blood monocytes in the development of AD remain unclear. In this study, we sought to investigate the alterations in the Aβ phagocytosis function of peripheral monocytes during ageing and in AD patients. A total of 104 cognitively normal participants aged 22-89 years, 24 AD patients, 25 age- and sex-matched cognitively normal (CN) subjects, 15 Parkinson's ...[more]

PMID: 33293506

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Project description:Alzheimer's disease begins about two decades before the onset of symptoms or neuron death, and is believed to be caused by pathogenic amyloid-? aggregates that initiate a cascade of molecular events culminating in widespread neurodegeneration. The microtubule binding protein tau may mediate the effects of amyloid-? in this cascade. Amyloid plaques comprised of insoluble, fibrillar amyloid-? aggregates are the most characteristic feature of Alzheimer's disease. However, the correspondence between the distribution of plaques and the pattern of neurodegeneration is tenuous. This discrepancy has stimulated the investigation of other amyloid-? aggregates, including soluble amyloid-? oligomers. Different soluble amyloid-? oligomers have been studied in several mouse models, but not systematically in humans. Here, we measured three amyloid-? oligomers previously described in mouse models-amyloid-? trimers, A?*56 and amyloid-? dimers-in brain tissue from 75 cognitively intact individuals, ranging from young children to the elderly, and 58 impaired subjects with mild cognitive impairment or probable Alzheimer's disease. As in mouse models, where amyloid-? trimers appear to be the fundamental amyloid-? assembly unit of A?*56 and are present in young mice prior to memory decline, amyloid-? trimers in humans were present in children and adolescents; their levels rose gradually with age and were significantly above baseline in subjects in their 70s. A?*56 levels were negligible in children and young adults, rose significantly above baseline in subjects in their 40s and increased steadily thereafter. Amyloid-? dimers were undetectable until subjects were in their 60s; their levels then increased sharply and correlated with plaque load. Remarkably, in cognitively intact individuals we found strong positive correlations between A?*56 and two pathological forms of soluble tau (tau-CP13 and tau-Alz50), and negative correlations between A?*56 and two postsynaptic proteins (drebrin and fyn kinase), but none between amyloid-? dimers or amyloid-? trimers and tau or synaptic proteins. Comparing impaired with age-matched unimpaired subjects, we found the highest levels of amyloid-? dimers, but the lowest levels of A?*56 and amyloid-? trimers, in subjects with probable Alzheimer's disease. In conclusion, in cognitively normal adults A?*56 increased ahead of amyloid-? dimers or amyloid-? trimers, and pathological tau proteins and postsynaptic proteins correlated with A?*56, but not amyloid-? dimers or amyloid-? trimers. We propose that A?*56 may play a pathogenic role very early in the pathogenesis of Alzheimer's disease.

Dataset Information

Amyloid-beta uptake by blood monocytes is reduced with ageing and Alzheimer's disease.

Publications

Amyloid-beta uptake by blood monocytes is reduced with ageing and Alzheimer's disease.

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