Soluble pre-fibrillar tau and β-amyloid species emerge in early human Alzheimer’s disease and track disease progression and cognitive decline

Abstract

Post-mortem investigations of human Alzheimer’s disease (AD) have largely failed to provide unequivocal evidence in support of the original amyloid cascade hypothesis, which postulated deposition of β-amyloid (Aβ) aggregates to be the cause of a demented state as well as inductive to tau neurofibrillary tangles (NFTs). Conflicting evidence suggests, however, that Aβ plaques and NFTs, albeit to a lesser extent, are present in a substantial subset of non-demented individuals. Hence, a range of soluble tau and Aβ species has more recently been implicated as the disease-relevant toxic entities. Despite the incorporation of soluble proteins into a revised amyloid cascade hypothesis, a detailed characterization of these species in the context of human AD onset, progression and cognitive decline has been lacking. Here, lateral temporal lobe samples (Brodmann area 21) of 46 human cases were profiled via tau and Aβ Western blot and native state dot blot protocols. Elevations in phospho-tau (antibodies: CP13, AT8 and PHF-1), pathological tau conformations (MC-1) and oligomeric tau (TOC1) agreed with medical diagnosis (non-AD cf. AD) and Braak stage classification (low, intermediate and high), alongside elevations in soluble Aβ species (MOAB-2 and pyro-glu Aβ) and a decline in levels of the amyloid precursor protein. Strong correlations were observed between individual Braak stages and multiple cognitive measures with all tau markers as well as total soluble Aβ. In contrast to previous reports, SDS-stable Aβ oligomers (*56) were not found to be reliable for all classifications and appeared likely to be a technical artefact. Critically, the robust predictive value of total soluble Aβ was dependent on native state quantification. Elevations in tau and Aβ within soluble fractions (Braak stage 2–3 cf. 0) were evident earlier than previously established in fibril-focused disease progression scales. Together, these data provide strong evidence that soluble forms of tau and Aβ co-localise early in AD and are closely linked to disease progression and cognitive decline.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1632-3) contains supplementary material, which is available to authorized users.

Early intraneuronal amyloid triggers neuron-derived inflammatory signaling in APP transgenic rats and human brain

“…Although the amyloid plaque represents a potent immunological structure within the brain, comprising an agglomerate of insoluble proteins, toxic cytokines, and complement factors, it is well-established that plaque-load is a poor correlate of cognitive decline, cell loss, and NFT density in disease-vulnerable brain regions (20,(86)(87)(88)(89)(90)(91). Rather, compared with amyloid plaques, increasing levels of soluble Aβ are a better predictor of synaptic dysfunction, cognitive deficits, and pathological tau when analyzed in the postmortem AD brain (16,(18)(19)(20). We propose that the incremental build-up of soluble and oligomeric iAβ may provoke a neuron-specific immune reaction, setting off a neuroinflammatory cascade at the earliest stages of AD.…”

“…This soluble pool of intraneuronal Aβ (iAβ) also increases in an age-dependent manner within the entorhinal cortex, a brain region regarded as the origin of AD neuropathological spread (13,15). Despite the fact that Aβ oligomers represent the most toxic amyloid species within the brain (16)(17)(18)(19)(20), the effects of progressive iAβ build-up have scarcely been studied, and information on how this soluble pool may influence AD susceptibility is lacking.…”

Interval timing is disrupted in female 5xFAD mice: An indication of altered memory processes

“…Alzheimer's disease (AD) is characterized by the progressive hippocampal and neocortical neurodegeneration that results in cognitive, affective, and motor disruptions (Buchman & Bennett, 2011;McKhann et al, 2011;Pini et al, 2016;Rosenberg, Nowrangi, & Lyketsos, 2015;Scheltens et al, 2016). Senile plaque and neurofibrillary tangle aggregations, as well as loss of basal forebrain cholinergic neurons, are found in the brains of AD patients (Auld, Kornecook, Bastianetto, & Quirion, 2002;Frankó, Joly, & Alzheimer's Disease Neuroimaging Initiative, 2013;Villemagne, Doré, Burnham, Masters, & Rowe, 2018) collectively contributing to dysfunctions in synaptic transmission (Baker-Nigh et al, 2015;Bloom, 2014;Hampel et al, 2018;Koss et al, 2016;Piccini et al, 2005;Willén, Sroka, Takahashi, & Gouras, 2017). The resultant decline in cognitive functions of AD patients is not limited to episodic memory but also encompasses executive functions and attention, starting in the early stages of the disease (Buckner, 2004;Kirova, Bays, & Lagalwar, 2015;Stopford, Thompson, Neary, Richardson, & Snowden, 2012;Storandt, 2008).…”

Oxidative stress in Alzheimer disease as a target for therapy

“…The hyperphosphorylation of tau protein takes place in pathologies commonly called tauopathies. Amyotrophic lateral sclerosis, corticobasal degeneration, dementia pugilistica, and fronto-temporal dementia can be introduced as tauopathies beside Alzheimer disease where hyperphosphorylation of tau protein also occurs (37)(38)(39)(40)(41). Tauopathy can be also revealed in Parkinson disease patients (42).…”