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

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 nondemented 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 [ 3 H]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 [ 3 H]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 [ 3 H]PK11195, and negatively correlated with [ 3 H]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.

In Vivo Cortical Microstructure: A Proxy for Tauopathy and Cognitive impairment in the Elderly with and without MCI/Dementia

“…We also show that increases in tau are broadly associated with decreases in ODI and NDI and increases in fISO. Our findings are supported by recent postmortem PET evidence showing a negative relationship between tau and synaptic density PET and a positive relationship between tau and neuroinflammation-related PET in the middle frontal gyrus (Brodmann area 46) of AD patient tissue 56 . While tau aggregation reflects AD’s direct etiology, fISO likely captures downstream neuroinflammatory processes, which are useful measures of cognitive decline in their own right and can supplement tau PET imaging.…”

Molecular pathology and synaptic loss in primary tauopathies: [18F]AV-1451 and [11C]UCB-J PET study

“…To understand the biphasic relationship between tau accumulation and synaptic density, one must consider other key players in synaptotoxicity in tauopathies, such as neuroinflammation 47 . Recent in vivo studies have confirmed the regional co-localisation of inflammation and [ 18 F]AV-1451 binding in PSP 48 , in line with previous in vivo 49,50 , and post mortem 51 reports of the tight interplay between neuroinflammation and tau accumulation in tauopathies. There is growing evidence that these two pathological processes affect synaptic function both independently and synergistically 40,42 .…”

TSPO Ligands PK11195 and Midazolam Reduce NLRP3 Inflammasome Activation and Proinflammatory Cytokine Release in BV-2 Cells

“…Under normal physiological conditions, TSPO expression is low in brain glial cells but is significantly increased in brain injury and inflammation, a feature that makes it particularly suitable for assessing active glial cells (Biswas et al, 2018 ; Werry et al, 2019 ). Significant increases in TSPO expression were found in many neurodegenerative diseases, such as Alzheimer’s disease (AD; Metaxas et al, 2019 ), Parkinson’s disease (PD; Gerhard, 2016 ), and Huntington’s disease (HD; Metaxas et al, 2019 ). However, the causal relationship between changes in TSPO protein expression and the occurrence of neurodegenerative diseases is still unclear.…”