Biology subjects

Pervushin, K.

Publications and source records attributed to Pervushin, K..

3 recordsLinked to original sources

bioRxiv2020

Conjugates of neuroprotective chaperone L-PGDS provide MRI contrast for detection of amyloid β-rich regions in live Alzheimer's Disease mouse model brain

Endogenous brain proteins can recognize the toxic oligomers of amyloid-{beta} (A{beta}) peptides implicated in Alzheimers disease (AD) and interact with them to prevent their aggregation. Lipocalin-type Prostaglandin D Synthase (L-PGDS) is a major A{beta}-chaperone protein in the human cerebrospinal fluid. Here we demonstrate that L-PGDS detects amyloids in diseased mouse brain. Conjugation of L-PGDS with magnetic nanoparticles enhanced the contrast for magnetic resonance imaging. We conjugated the L-PGDS protein with ferritin nanocages to detect amyloids in the AD mouse model brain. We show here that the conjugates administered through intraventricular injections co-localize with amyloids in the mouse brain. These conjugates can target the brain regions through non-invasive intranasal administration, as shown in healthy mice. These conjugates can inhibit the aggregation of amyloids in vitro and show potential neuroprotective function by breaking down the mature amyloid fibrils.

biochemistry↗

bioRxiv2020

Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene-dose-sensitive AD-suppressor in human brain

A population of >6 million people worldwide at high risk of Alzheimers disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of {beta}-amyloid-(A{beta})-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar A{beta} deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome-21-gene BACE2, but prevented by combined chemical {beta} and {gamma}-secretase inhibition. We found that T21-organoids secrete increased proportions of A{beta}-preventing (A{beta}1-19) and A{beta}-degradation products (A{beta}1-20 and A{beta}1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1-inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in [~]30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.

neuroscience↗

bioRxiv2020

Xenobiotic compounds modulate cytotoxicity of Aβ amyloids and interact with neuroprotective chaperone L-PGDS

A positive association of the exposure to different classes of xenobiotics such as commonly prescribed drugs and polycyclic aromatic hydrocarbons (PAH) typically those found in air pollution-related particulate matter with Alzheimers disease (AD) may point to direct physical interaction of those compounds with the amyloid formation and clearance processes. In this study, for the first time, we provide evidence of such interactions for three representative compounds from prescription drugs and air pollution, e.g. anticholinergic drugs Chlorpheniramine, a common antihistamine, and Trazodone, an antidepressant as well as 9,10-PQ, a common PAH anthraquinone abundantly present in diesel exhaust and associated with AD. We demonstrate that these three compounds bind to the lipophilic compound carrier and neuroprotective amyloid beta (A{beta}) chaperone lipocalin-type prostaglandin D synthase (L-PGDS) with high affinity attenuating its neuroprotective chaperone function with Chlorpheniramine exhibiting markedly stronger inhibitory effects. We also show that these compounds directly interact with A{beta}(1-40) increasing the fibrils yield with altered fibril morphology and increased the cytotoxicity of the resulting fibrils. We propose that exposure to some xenobiotics in the peripheral tissues such as gut and lungs might result in the accumulation of these compounds in the brain facilitated by the carrier function of L-PGDS. This might lead to attenuation of its neuroprotective function and direct modification of A{beta} amyloid morphology and cytotoxicity. This hypothesis might provide a mechanistic link between exposure to xenobiotic compounds and the increased risk of Alzheimers disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/920884v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@14a4d92org.highwire.dtl.DTLVardef@12aadeeorg.highwire.dtl.DTLVardef@100e5e1org.highwire.dtl.DTLVardef@1f44b9b_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗