Brain amyloid-β oligomers in ageing and Alzheimer’s disease

Abstract

Alzheimer's disease begins about two decades before the onset of symptoms or neuron death, and is believed to be caused by pathogenic amyloid-β aggregates that initiate a cascade of molecular events culminating in widespread neurodegeneration. The microtubule binding protein tau may mediate the effects of amyloid-β in this cascade. Amyloid plaques comprised of insoluble, fibrillar amyloid-β 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-β aggregates, including soluble amyloid-β oligomers. Different soluble amyloid-β oligomers have been studied in several mouse models, but not systematically in humans. Here, we measured three amyloid-β oligomers previously described in mouse models-amyloid-β trimers, Aβ*56 and amyloid-β 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-β trimers appear to be the fundamental amyloid-β assembly unit of Aβ*56 and are present in young mice prior to memory decline, amyloid-β 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. Aβ*56 levels were negligible in children and young adults, rose significantly above baseline in subjects in their 40s and increased steadily thereafter. Amyloid-β 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 Aβ*56 and two pathological forms of soluble tau (tau-CP13 and tau-Alz50), and negative correlations between Aβ*56 and two postsynaptic proteins (drebrin and fyn kinase), but none between amyloid-β dimers or amyloid-β trimers and tau or synaptic proteins. Comparing impaired with age-matched unimpaired subjects, we found the highest levels of amyloid-β dimers, but the lowest levels of Aβ*56 and amyloid-β trimers, in subjects with probable Alzheimer's disease. In conclusion, in cognitively normal adults Aβ*56 increased ahead of amyloid-β dimers or amyloid-β trimers, and pathological tau proteins and postsynaptic proteins correlated with Aβ*56, but not amyloid-β dimers or amyloid-β trimers. We propose that Aβ*56 may play a pathogenic role very early in the pathogenesis of Alzheimer's disease.

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

“…Brain specimens and subject characteristics were described previously (65). The Religious Orders Study was approved by the Institutional Review Board of Rush University Medical Center and all participants gave informed consent, signed an Anatomical Gift Act for organ donation, and signed a repository consent to allow data and biospecimen sharing.…”

Alternative Selection of β-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid β-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations within the Aβ Sequence

“…A␤ is the major protein component of senile plaques observed in the brain of Alzheimer's disease (AD) subjects, and soluble A␤ oligomer(s) are thought to impair synaptic functions prior to A␤ deposition in the brain (17)(18)(19). Therefore, to understand AD pathogenesis and develop effective AD ther-…”

“…1B). To this end, we transiently expressed mAPP-(695) and hAPP-(695) in mouse N2a and human SHSY5Y neuroblastoma cells, and then analyzed the secreted A␤ forms by MALDI-TOF/MS following immunoprecipitation with pan-A␤ antibody 4G8, which recognizes an epitope within the A␤ (17)(18)(19)(20)(21)(22)(23)(24) region. We identified several A␤ species in which the amino-terminal amino acid was Asp (A␤(1-XX), a product of ␤-site cleavage) or Glu (A␤(11-XX), a product of ␤Ј-site cleavage).…”

“…into the medium (1 ml) and mixed mouse CSF (C57BL/6, 100 l) were recovered by immunoprecipitation with anti-pan A␤ antibody 4G8, which was raised to A␤ [17][18][19][20][21][22][23][24] epitope (BioLegend, San Diego, CA) plus Protein G-Sepharose 4B (GE Healthcare Bio-Sciences) following pre-clearing with the same beads without antibody. The beads were sequentially washed, and the bound proteins were eluted with trifluoroacetic acid/acetonitrile/water (1:20: 20) saturated with sinapinic acid as described (51).…”

“…Cleavage of CTF␤Ј/C89 by ␥-secretase yields A␤(11-XX), which lacks the first 10 amino acids of the A␤ domain. This ␤Ј-site cleavage of APP is also thought to be amyloidolytic, because the structural analysis suggests that A␤(11-40) and A␤(11-42) are less toxic than A␤(1-40) and A␤(1-42) (14), and the A␤(11-42) showed reduced neurotoxicity compared with A␤(1-42) and A␤(3-42) in a study with transgenic fly (15), although the neurotoxicity of A␤(11-XX) in human brain is controversial (16).A␤ is the major protein component of senile plaques observed in the brain of Alzheimer's disease (AD) subjects, and soluble A␤ oligomer(s) are thought to impair synaptic functions prior to A␤ deposition in the brain (17)(18)(19). Therefore, to understand AD pathogenesis and develop effective AD ther-…”