Sortilin Fragments Deposit at Senile Plaques in Human Cerebrum

Abstract

Genetic variations in the vacuolar protein sorting 10 protein (Vps10p) family have been linked to Alzheimer’s disease (AD). Here we demonstrate deposition of fragments from the Vps10p member sortilin at senile plaques (SPs) in aged and AD human cerebrum. Sortilin changes were characterized in postmortem brains with antibodies against the extracellular and intracellular C-terminal domains. The two antibodies exhibited identical labeling in normal human cerebrum, occurring in the somata and dendrites of cortical and hippocampal neurons. The C-terminal antibody also marked extracellular lesions in some aged and all AD cases, appearing as isolated fibrils, mini-plaques, dense-packing or circular mature-looking plaques. Sortilin and β-amyloid (Aβ) deposition were correlated overtly in a region/lamina- and case-dependent manner as analyzed in the temporal lobe structures, with co-localized immunofluorescence seen at individual SPs. However, sortilin deposition rarely occurred around the pia, at vascular wall or in areas with typical diffuse Aβ deposition, with the labeling not enhanced by section pretreatment with heating or formic acid. Levels of a major sortilin fragment ~15 kDa, predicted to derive from the C-terminal region, were dramatically elevated in AD relative to control cortical lysates. Thus, sortilin fragments are a prominent constituent of the extracellularly deposited protein products at SPs in human cerebrum.

Lack of human-like extracellular sortilin neuropathology in transgenic Alzheimer’s disease model mice and macaques

“…Further understanding of the neurobiological and neuropathological roles played by this family of proteins might extend novel AD diagnostic and therapeutic options. We recently reported that putative C-terminal fragments from sortilin can deposit in aged and AD human brains as extracellular lesions morphologically appearing as senile plaques [ 61 ]. The deposition occurs fairly selectively at neuritic amyloid plaques, as visualized with an antibody (catalog number ab16640; Abcam, Cambridge, UK) targeting the intracellular C-terminal domain of sortilin, which is evolutionarily conserved among mammals.…”

Progress in Human Brain Banking in China

“…Sun et al from Tiantan Hospital of Capital Medical University demonstrate that diffuse intrinsic pontine glioma exhibits the cell-biological and molecular signatures of fetal hindbrain-derived neural progenitor cells [30]. The research reports included in the current special issue, together with others recently published elsewhere [31][32][33][34][35], clearly showcase that brain banking in China can support important original investigations for the better understanding of human brain structure and function. It can be expected that, with further progress on this front, additional discoveries will emerge and help unravel the underpinnings of major neurological, psychiatric, and developmental brain diseases affecting the Chinese people.…”

Hydrogen Inhalation Attenuates Oxidative Stress Related Endothelial Cells Injury After Subarachnoid Hemorrhage in Rats

“…Brain samples were cut into 30 µm thick coronal sections and collected in serial sets as previously described using a cryostat (Leica CM3050S, Buffalo Grove, IL, United States). Consecutive sections from each animal were stained with cresyl violet (Nissl stain), hematoxylin/eosin (HE) and primary antibodies with the avidin-biotin complex (ABC) method or fluorescent-tagged secondary antibodies as previously described (Hu et al, 2017). The primary antibodies used including the following: NLRP3 (1:200, Cat#ab4207, Abcam, United States), ASC (1:200, Cat#sc-51414, Abcam, United States), 8-OHdG (1:200, Cat#ab48508, Abcam, United States), DCX (1:200, Cat#ab18723, Abcam, United States), and fibrinogen (1:500, Cat# LS-B11024, Lifespan, United States).…”