Pyroglutamylated amyloid-β is associated with hyperphosphorylated tau and severity of Alzheimer’s disease

Abstract

Pyroglutamylated amyloid-β (pE(3)-Aβ) has been suggested to play a major role in Alzheimer's disease (AD) pathogenesis as amyloid-β (Aβ) oligomers containing pE(3)-Aβ might initiate tau-dependent cytotoxicity. We aimed to further elucidate the associations among pE(3)-Aβ, full-length Aβ and hyperphosphorylated tau (HP-τ) in human brain tissue. We examined 41 post mortem brains of both AD (n = 18) and controls. Sections from frontal and entorhinal cortices were stained with pE(3)-Aβ, HP-τ and full-length Aβ antibodies. The respective loads were assessed using image analysis and western blot analysis was performed in a subset of cases. All loads were significantly higher in AD, but when using Aβ loads as independent variables only frontal pE(3)-Aβ load predicted AD. In frontal and entorhinal cortices pE(3)-Aβ load independently predicted HP-τ load while non-pE(3)-Aβ failed to do so. All loads correlated with the severity of AD neuropathology. However, partial correlation analysis revealed respective correlations in the frontal cortex only for pE(3)-Aβ load only while in the entorhinal cortex respective correlations were seen for both HP-τ and non-pE(3)-Aβ loads. Mini Mental State Examination scores were independently predicted by entorhinal HP-τ load and by frontal pE(3)-Aβ load. Here, we report an association between pE(3)-Aβ and HP-τ in human brain tissue and an influence of frontal pE(3)-Aβ on both the severity of AD neuropathology and clinical dementia. Our findings further support the notion that pE(3)-Aβ may represent an important link between Aβ and HP-τ, and investigations into its role as diagnostic and therapeutic target in AD are warranted.

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

“…Furthermore, pyro-glu Aβ only weakly correlated with individual Braak stages and failed to correlate with any measure of cognition. This is largely at odds with previous reports of disease specificity [52] and toxicity [61], although in agreement with previous work where a correlation was established between levels of pyro-glu-modified Aβ and tau phosphorylation [52]. …”

Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons

“…The predominance of pE-A␤ in the central core of plaques suggests an early involvement in amyloid deposition in the AD brain (52), whereas correlation between pE-A␤ and a decline in Mini Mental State Examination scores implicate pE-A␤ cytotoxicity in AD neurodegeneration (53,54). In parallel, markers of oxidative stress are among the earliest detectable pathological changes in transgenic AD mouse models (55) and the human AD brain (36,56,57), with numerous lines of evidence implicating A␤ as a central contributor to oxidative stress in AD (58,59).…”

An anti-pyroglutamate-3 Aβ vaccine reduces plaques and improves cognition in APPswe/PS1ΔE9 mice

“…Also, it has been demonstrated that pGlu-3 Aβ may act as a nidus for template-induced protein misfolding and oligomerization, both with itself and with free Aβ1-42 to generate cytotoxic low-molecular weight oligomers (Nussbaum et al, 2012). Recently, QC expression and pGlu-3 Aβ accumulation in human AD brain has been shown to correlate with cognitive decline (Morawski et al, 2014, Pivtoraiko et al, 2014) and tau pathology (Mandler et al, 2014). Thus, cumulating evidence from human post-mortem tissue and mouse models suggest pGlu-modified Aβ as a species causally involved in AD progression and cognitive decline (Rijal Upadhaya et al, 2014, Saido et al, 1995).…”