Association of Neuropathological Markers in the Parietal Cortex With Antemortem Cognitive Function in Persons With Mild Cognitive Impairment and Alzheimer Disease

Abstract

<jats:p>The associations between cognitive function and neuropathological markers in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD) remain only partly defined. We investigated relationships between antemortem global cognitive scores and β-amyloid (Aβ), tau, TDP-43, synaptic proteins and other key AD neuropathological markers assessed by biochemical approaches in postmortem anterior parietal cortex samples from 36 subjects (12 MCI, 12 AD and 12 not cognitively impaired) from the Religious Orders Study. Overall, the strongest negative correlation coefficients associated with global cognitive scores were obtained for insoluble phosphorylated tau (r2 = −0.484), insoluble Aβ42 (r2 = −0.389) and neurofibrillary tangle counts (r2 = −0.494) (all p &amp;lt; 0.001). Robust inverse associations with cognition scores were also established for TDP-43-positive cytoplasmic inclusions (r2 = −0.476), total insoluble tau (r2 = −0.385) and Aβ plaque counts (r2 = −0.426). Sarkosyl (SK)- or formic acid (FA)-extracted tau showed similar interrelations. On the other hand, synaptophysin (r2 = +0.335), pS403/404 TDP-43 (r2 = +0.265) and septin-3 (r2 = +0.257) proteins positively correlated with cognitive scores. This study suggests that tau and Aβ42 in their insoluble aggregated forms, synaptic proteins and TDP-43 are the markers in the parietal cortex that are most strongly associated with cognitive function. This further substantiates the relevance of investigating these markers to understand the pathogenesis of AD and develop therapeutic tools.</jats:p>

Repurposing beta3-adrenergic receptor agonists for Alzheimer’s disease: Beneficial effects on recognition memory and amyloid pathology in a mouse model

“…We subsequently assessed the effect of the β3AR agonist on proteins implicated in the production (beta-secretase 1 (BACE-1), amyloid precursor protein (APP), APP C-terminal, sAPPα) and clearance or degradation (low density lipoprotein receptor related protein 1 (LRP1), receptor of advanced glycation end products (RAGE), insulin degrading enzyme (IDE), X11α) of Aβ peptides (Table S1) (Donahue et al, 2006;Farris et al, 2003;Selkoe and Hardy, 2016). Levels of BACE-1, IDE, LRP1 and RAGE in the hippocampus did not differ between groups, whereas those of X11α were lower in 3xTg-AD mice compared to NonTg mice (Table S1) as observed in the brain of AD individuals (Tremblay et al, 2017).…”

“…Synaptic deficits are one of the earliest markers of AD, correlating with symptoms (Arendt, 2009;Tremblay et al, 2017). The levels of synaptic proteins were not modified by the treatment (Table S1).…”

“…The remaining pellets from ultracentrifugation were resuspended in formic acid, resulting in a detergent-insoluble fraction (insoluble proteins fraction). The resultant suspension was sonicated and centrifuged (13,000g, 20 min, 4 °C), acid formic was evaporated and proteins were either solubilized in Laemmli's buffer for Western blot or in a 5 M guanidium solution in Tris-HCl 50 mM for Aβ peptides ELISAs as previously described (Tremblay et al, 2017). Proteins from the BAT were extracted in the lysis buffer only.…”

Characterization of a 3xTg‐AD mouse model of Alzheimer's disease with the senescence accelerated mouse prone 8 (SAMP8) background

“…Given that hyperphosphorylation of tau is a key diagnostic marker of AD and a major correlate of cognitive symptoms (Bennett, Schneider, Wilson, Bienias, & Arnold, ; Braak and Braak, ; Tremblay et al, ) we sought to examine whether the SAMP8 genetic background would potentiate the development of tau pathology in 3xTg‐AD mice. Levels of soluble tau phosphorylated at Thr231 (AT180) (normalized to total tau) were higher in the parieto‐temporal cortex of female P8/3xTg‐AD mice compared to female R1/3xTg‐AD controls (total tau‐normalized AT180, +277% vs. female R1/3xTg‐AD mice; p = 0.0139; Kruskal‐Wallis‐ANOVA/Dunnett; Figure b), a difference not observed in males or in NonTg groups.…”

“…Clinicopathological studies show a strong association between cerebral NFTs, which are primarily composed of misfolded and abnormally hyperphosphorylated aggregated tau, and the severity of dementia in human AD subjects (Braak and Braak, ; Tremblay et al, ; Bennett et al, ; Nelson et al, ). Besides aging factors, sex differences have also been suspected; both higher prevalence and incidence of AD in women have been reported in epidemiological studies (Snyder et al ; Kim et al, ; Mielke, Vemuri, & Rocca, ).…”