It was also demonstrated that fibril-free AβO solutions are essential for memory loss (Brito-Moreira et al. 2017), while the fibrillar Aβ in amyloid deposits is not the active factor affecting the cognition (Martins et al. 2008).
In cultures of mature hippocampal neurons, soluble AβOs caused a rapid, substantial loss of surface IRs, especially on dendrites (Zhao et al. 2010).
In addition, the load of AβO deposits significantly correlated with fibrillar Aβ plaque deposition as well as with neuronal loss and numbers of astrocytes, although not with memory deficits.
Despite enhanced Aβ42 accumulation in AD brain (Lewczuk et al. 2003), concentrations of monomeric Aβ42 in the CSF of AD patients are decreased
The histopathological changes in the brain include the presence of extracellular amyloid plaques consisted of various peptide variants of amyloid β (Aβ) and accumulation of intracellular neurofibrillary tangles (NFTs) composed mainly of phosphorylated Tau proteins (pTau), localized predominantly in neurons (reviewed by Serrano-Pozo et al. 2011).
Amyloid hypothesis is supported by the fact that progressive Aβ deposition is observed in early, preclinical stages of AD and, finally, in all AD patients.
The presence of amyloid deposits, as the main factor leading to damage of the nerve tissue (amyloid hypothesis) has been postulated for over 25 years (recently reviewed in Selkoe and Hardy 2016).
These Aβ deposits lead to subsequent molecular and cellular alterations, such as NTFs, neuronal dystrophy, or microgliosis, i.e., pathological events that are closer to dementia and more relevant to neuronal dysfunction.
Furthermore, the authors demonstrated significant, negative correlation of AβO number with the MMSE scores, what indicates that sFIDA readout seems to reflect the severity of AD, similar to the results described above.
On the contrary, no relationship between total Aβ plaque burden and number of astrocytes or neurons was found (da Rocha-Souto et al. 2011).
It was demonstrated that Aβ42 oligomers, but not monomers, significantly altered Ca2+ release from intracellular stores (Lazzari et al. 2015), what induced intracellular Ca2+ increase in neurons via the complex PrPC–mGluR5, with harmful effects on synaptic transmission (Beraldo et al. 2016).
Moreover, it was postulated that AβOs may trigger a harmful cascade damaging neurons and synapses (Morris et al. 2014).
Soluble Aβ oligomers may cause a highly selective neuronal death accelerated by increasing exposure to AβOs (Lambert et al. 1998).
In normal rats, impaired memory of a learned behavior was observed after intraventricular application of soluble oligomers of Aβ42 isolated directly from human AD brains (Shankar et al. 2008). Furthermore, AβO injections resulted in reduction of a synapse number and their function in dose-dependent manner. It also led to the inhibition of LTP and enhancement of long-term synaptic depression (LTD) in rodent hippocampus (Shankar et al. 2008).
These results are in line with findings of Koffie et al. (2009), who revealed that AβOs surrounding plaques contribute to synapse loss in a mouse model of AD.
It was also shown that soluble AβOs may directly trigger dysfunction of neural signaling, which leads to early memory loss and the progression of dementia in AD.
In very early stages of AD pathology, before the appearance of amyloid plaques, oligomers assemble perisomatically, rather than intracellularly, surrounding individual diffuse neurons.
They revealed increases in AβOs and soluble TNF-R plasma levels that accurately differentiated mild AD patients from control subjects and to some extent from amnestic mild cognitive impairment (aMCI) patients.
Moreover, in brain slices, AβOs rapidly inhibited long-term potentiation (LTP) of synapses (Klein et al. 2001).
AβOs can trigger changes in Tau protein characteristic for AD (Shankar et al. 2008). They induce hyperphosphorylation of Tau at AD-specific epitopes and cause neuritic dystrophy in cultured neurons.
Furthermore, it was demonstrated that AβO may not only injure the neurites of brain neurons, but also activate microglia and astrocyte response (Sondag et al. 2009).
Excessive activation of NMDAR by soluble AβOs triggers disproportionate influx of Ca2+ into neurons, which leads to excitotoxicity, mitochondrial dysfunction, and loss of synapses (Zhao et al. 2004).
Soluble AβOs, but not monomers, mediate the internalization of the GluA1/GluA2 subunits by endocytosis (Zhang et al. 2011), leading to synaptic dysfunction (Hsieh et al. 2006).
Synapse targeting of AβOs involves activation of p75NTR.
The levels of HMW AβOs in AD or MCI patients were significantly higher than in normal controls and correlated inversely with MMSE score.
LMW oligomers led to a decrease in the neuronal levels of β2ARs, activated brain microglia, and induced impaired hippocampal LTP in mice in vivo (Yang et al. 2017).
Using a novel misfolded protein assay for the detection of soluble oligomers composed of Aβx-40 and Aβx-42 peptides, Gao and co-workers demonstrated also increased levels of oligomeric Aβ40 in CSF, which may be a potential biomarker for the diagnosis of AD (Gao et al. 2010).
These results suggest that circulating Aβ40 oligomers, and not only Aβ42 oligomers, could be a potential new biomarker in early AD.
The risk factors of AD include: increasing age, vascular factors such as smoking, obesity, and diabetes (Reitz and Mayeux 2014) as well as genetic mutations.
An exponential increase of brain levels of AβOs in aging mice was observed.
PrPC was identified as AβO co-receptor, which mediates an impairment of synaptic plasticity by AβOs, although the infectious form PrPSc conformation is not necessary (Lauren et al. 2009).
Moreover, PrPC inhibits formation fibrillary form of Aβ, trapping Aβ in an oligomeric state (Younan et al. 2013).
However, a significant risk of AD development is related to certain genetic changes: the sporadic form of AD can be associated with the presence of apolipoprotein E (APOE) ε4 genotype (Holtzman et al. 2012; Spinney 2014), whereas the familial Alzheimer’s disease (FAD) can be linked to mutations in presenilin1 (PS1), presenilin2 (PS2), and amyloid precursor protein (APP) genes (reviewed by Hardy and Gwinn-Hardy 1998).
AD belongs to a large group of neurodegenerative diseases (NDs) characterized by cognitive impairment and progressive synaptic damage accompanied by neuronal loss.
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.