Increased Inflammation and Unchanged Density of Synaptic Vesicle Glycoprotein 2A (SV2A) in the Postmortem Frontal Cortex of Alzheimer's Disease Patients.

Athanasios Metaxas,Bente Finsen,Anne M Landau,Sultan Darvesh,Sanne R R Briting,Camilla Thygesen

doi:10.3389/fncel.2019.00538

Abstract

Sections from the middle frontal gyrus (Brodmann area 46) of autopsy-confirmed Alzheimer’s disease (AD) patients and non-demented subjects were examined for the prevalence of hallmark AD pathology, including amyloid-β (Aβ) plaques, phosphorylated tau (pTau) tangles, neuroinflammation and synaptic loss (n = 7 subjects/group). Dense-core deposits of Aβ were present in all AD patients (7/7) and some non-demented subjects (3/7), as evidenced by 6E10 immunohistochemistry. Levels of Aβ immunoreactivity were higher in AD vs. non-AD cases. For pTau, AT8-positive neurofibrillary tangles and threads were exclusively observed in AD patient tissue. Levels of [3H]PK11195 binding to the translocator protein (TSPO), a marker of inflammatory processes, were elevated in the gray matter of AD patients compared to non-demented subjects. Levels of [3H]UCB-J binding to synaptic vesicle glycoprotein 2A (SV2A), a marker of synaptic density, were not different between groups. In AD patients, pTau immunoreactivity was positively correlated with [3H]PK11195, and negatively correlated with [3H]UCB-J binding levels. No correlation was observed between Aβ immunoreactivity and markers of neuroinflammation or synaptic density. These data demonstrate a close interplay between tau pathology, inflammation and SV2A density in AD, and provide useful information on the ability of neuroimaging biomarkers to diagnose AD dementia.

Highlights

Despite considerable advances in biological fluid and brain imaging biomarkers, autopsy remains the most reliable means of obtaining a definitive diagnosis of dementia due to Alzheimer’s disease (AD)
Autopsy studies demonstrate that aggregated Aβ and phosphorylated tau (pTau) can be detected in certain brain areas of cognitively intact individuals by the third to fourth decades of life (Braak and Braak, 1997; Braak et al, 2011)
Our results show that there is increased inflammation in Brodmann area 46 in AD, while synaptic vesicle glycoprotein 2A (SV2A) levels remain unchanged

Summary

Introduction

Despite considerable advances in biological fluid and brain imaging biomarkers, autopsy remains the most reliable means of obtaining a definitive diagnosis of dementia due to Alzheimer’s disease (AD). Biomarker studies in subjects with normal cognition indicate that the accumulation of Aβ may precede the onset of memory decline by at least a decade (Jansen et al, 2018). Autopsy studies demonstrate that aggregated Aβ and pTau can be detected in certain brain areas of cognitively intact individuals by the third to fourth decades of life (Braak and Braak, 1997; Braak et al, 2011). As the pathognomonic lesions of AD are present in a significant proportion of individuals with normal cognition, dissociating AD from physiological brain aging represents a major challenge in the dementia research field. The assumption that Aβ and pTau biomarker-positive subjects are on a path to developing dementia remains a point of contention (Nelson et al, 2011; Franceschi et al, 2018)

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