Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Abstract

Amyloid-b (Ab) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, Ab and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases with high levels of AD-related pathology were included to determine factors that confer protection from clinical symptoms. Flow cytometric analysis of synaptosome preparations was used to quantify Ab and p-tau in large populations of individual synaptic terminals. Soluble Ab oligomers were assayed by a single antibody sandwich enzyme-linked immunosorbent assay. Total in situ Ab was elevated in patients with early-and late-stage AD dementia, but not in high pathology nondemented controls compared with age-matched normal controls. However, soluble Ab oligomers were highest in early AD synapses, and this assay distinguished early AD cases from high pathology controls. Overall, synapse-associated p-tau did not increase until late-stage disease in human and transgenic rat cortex, and p-tau was elevated in individual Ab-positive synaptosomes in early AD. These results suggest that soluble oligomers in surviving neocortical synaptic terminals are associated with dementia onset and suggest an amyloid cascade hypothesis in which oligomeric Ab drives phosphorylated tau accumulation and synaptic spread. These results indicate that antiamyloid therapies will be less effective once p-tau pathology is developed. (Am J Pathol 2016, 186: 185e198; http://dx.doi.org/10.1016/j.ajpath.2015 A large body of evidence indicates that soluble oligomers of amyloid-b (Ab) are the primary toxic peptides that initiate downstream tau pathology in the amyloid cascade hypothesis of Alzheimer disease (AD). 1,2 However, the time course and severity of AD dementia have been generally found to correlate with neurofibrillary tangle development rather than plaque appearance, 3e8 although a few studies have linked plaques with early cognitive decline. 9e12 Soluble oligomeric

Molecular and cellular pathophysiology of preclinical Alzheimer’s disease

“…During the last few years, oligomeric Aβ species have been suggested to be one of the triggering mechanism for the synaptic impairment and tau phosphorylation in AD [8, 58] [59]. Cortical levels of Aβ oligomers accumulate in MCI and mild to moderate AD compared to age matched non-demented controls [60], correlate with severity of cognitive impairment, Braak staging, and lower levels of presynaptic and postsynaptic proteins [61].…”

“…Cortical levels of Aβ oligomers accumulate in MCI and mild to moderate AD compared to age matched non-demented controls [60], correlate with severity of cognitive impairment, Braak staging, and lower levels of presynaptic and postsynaptic proteins [61]. Oligomeric Aβ within synaptic terminals is associated with the accumulation of hyperphosphorylated tau in AD [59]. Interestingly, dimeric Aβ induces tau phosphorylation and dystrophic axonal profiles [62], suggesting a prion-like seeding or propagation mechanism underlying AD pathogenesis [63] or that selectively vulnerable subcortical long projection neurons may be sensitive to retrograde toxicity of Aβ oligomers.…”

Comparative pathobiology of β-amyloid and the unique susceptibility of humans to Alzheimer's disease

“…Genetic, pathologic, and biochemical evidence indicates that the aggregation of the β-amyloid peptide (Aβ) is a key factor in the pathogenesis of AD (Bateman, et al, 2012,Bilousova, et al, 2016,Hardy and Selkoe, 2002,Holtzman, et al, 2011,Nelson, et al, 2012). Aβ is an amphiphilic peptide, most often 40 or 42 amino acids in length, that is cleaved from the Aβ-precursor protein (APP); in AD, Aβ self-assembles into oligomers, protofibrils, and amyloid fibrils in the brain parenchyma and vasculature (Bitan, et al, 2005,Catalano, et al, 2006,Ferreira, et al, 2015,Hamley, 2012,Kuo, et al, 1996,Revesz, et al, 2003,Selkoe, 2011).…”

“…However, evidence from genetic, in vivo imaging and biochemical studies pinpoints the misfolding and aggregation of Aβ as the earliest critical event in the ontogeny of AD (Bateman, et al, 2012,Bilousova, et al, 2016,Holtzman, et al, 2011,Nelson, et al, 2012,Selkoe, 2011). Importantly, emerging analyses of Aβ and tau biomarkers indicate that the pathogenic cascade leading from Aβ accumulation to tauopathy and dementia begins in the brain more than a decade prior to the onset of clinical signs and symptoms (Bateman, et al, 2012,Buchhave, et al, 2012,Holtzman, et al, 2011,Jack and Holtzman, 2013,Sperling, et al, 2013).…”

What amyloid ligands can tell us about molecular polymorphism and disease

“…Variable rates of disease progression and differences in phenotype of idiopathic Alzheimer’s disease could result from different relative proportions of the morphotypes. Furthermore, in addition to the classical insoluble fibrillar forms of Aβ and tau, soluble oligomeric forms of the proteins also are present in the AD brain (Bilousova, et al, 2016, Catalano, et al, 2006, Lue, et al, 1999, McLean, et al, 1999, Wang, et al, 1999). Rapid clinical progression has been connected with a particular Aβ oligomer size distribution, conformational states, and stabilities (Cohen, et al, 2016, Cohen, et al, 2015).…”