Biology subjects

Portelius, E.

Publications and source records attributed to Portelius, E..

4 recordsLinked to original sources

bioRxiv2022

Genetic mapping of APP and amyloid-β biology modulation by trisomy 21

Individuals who have Down syndrome frequently develop early onset Alzheimers disease, a neurodegenerative condition caused by the build-up of aggregated amyloid-{beta} and tau proteins in the brain. Amyloid-{beta} is produced by APP, a gene located on chromosome 21. People who have Down syndrome have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of Alzheimers disease in these individuals. Here we use a combination of next-generation mouse models of Down syndrome (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of amyloid-{beta} accumulation (AppNL-F) to determine how chromosome 21 genes other than APP modulate APP/amyloid-{beta} in the brain when in three copies. We demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate amyloid-{beta} accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene/genes causing this decrease in amyloid-{beta} accumulation and investigate the role of two lead candidate genes Dyrk1a and Bace2. Thus an additional copy of chromosome 21 genes, other than APP, can modulate APP/amyloid-{beta} in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD-DS compared to those who have familial AD caused by triplication of APP.

neuroscience↗

bioRxiv2021

Plasma amyloid beta ratios in autosomal dominant Alzheimers disease: the influence of genotype

In-vitro studies of autosomal dominant Alzheimers disease (ADAD) implicate longer A{beta} peptides in pathogenesis, however less is known about the behaviour of ADAD mutations in-vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from ADAD family members who were at-risk of inheriting a mutation or were already symptomatic. We tested for differences in plasma A{beta}42:38, 38:40 and 42:40 ratios between Presenilin1 (PSEN1) and Amyloid Precursor Protein (APP) carriers. We examined the relationship between plasma and in-vitro models of A{beta} processing and, among PSEN1 carriers, tested for associations with parental age at onset (AAO). 39 participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma A{beta} between APP and PSEN1: higher A{beta}42:38 in PSEN1 versus APP (p<0.001) and non-carriers (p<0.001); higher A{beta}38:40 in APP versus PSEN1 (p<0.001) and non-carriers (p<0.001), while A{beta}42:40 was higher in APP and PSEN1 compared to non-carriers (both p<0.001). A{beta} profiles were reasonably consistent in plasma and cell lines. Within PSEN1, sex-adjusted models demonstrated negative associations between (i)A{beta}42:40 (ii)A{beta}42:38 and parental AAO. In-vivo differences in A{beta} processing between APP and PSEN1 provide insights into ADAD pathophysiology which can inform therapy development.

neuroscience↗

bioRxiv2020

Mutations in the juxtamembrane segment of the cholesterol-binding site of APP alter its processing and promotes production of shorter, less toxic Aβ peptides.

BackgroundThe brains of patients with Alzheimers disease (AD) reveal increased cellular membrane levels of cholesterol. Correspondingly, we previously showed that elevating levels of membrane cholesterol in neuronal cultures recapitulates early AD phenotypes including excessive cleavage of amyloid {beta} (A{beta}) peptides from the amyloid precursor protein (APP). Here we aimed to evaluate how the presence of a cholesterol-binding site (CBS) in the transmembrane and juxtamembrane regions of APP regulates its processing. MethodsWe generated seven single and two double APP mutants at amino acid positions 22, 26, 28, 29, 33, 39 of the A{beta} sequence changing the charge and/or hydrophobicity of the targeted amino acids. HEK293T cells were transfected with APP constructs and secreted A{beta} peptides were measured using ELISA and mass spectrometry (MS). APP processing in normal and high cholesterol condition, and endocytosis were assessed in stably expressing APPwt and APPK28A HEK293T clones. Finally, we measured the binding of synthetic peptides derived from the A{beta} sequence to cholesterol-rich exosomes purified from control HEK293T cells. ResultsMost mutations triggered a reduction in the production of A{beta}40 and A{beta}42 peptides, whereas only juxtamembrane mutants resulted in the generation of shorter A{beta} peptides. We confirmed by mass spectrometry this specific change in the profile of secreted A{beta} peptides for the most characteristic APPK28A mutant. A transient increase of plasma membrane cholesterol enhanced the production of A{beta}40 by APPWT, an effect absent with APPK28A. The enzymatic activity of -, {beta}- and {gamma}-secretases remained unchanged in cells expressing APPK28A. Similarly, APPK28A subcellular localization in early endosomes did not differ to APPWT. Finally, WT but not CBS mutant A{beta} derived peptides bound to cholesterol-rich exosomes. ConclusionsTaken together, these data reveal a major role of the juxtamembrane region of APP in binding to cholesterol and accordingly in the regulation of APP processing. Binding of cholesterol to K28 could staple APP to the juxtamembrane region thereby permitting access to {gamma}-secretase cleavage at positions 40-42. The APPK28 mutant would lie deeper in the membrane, facilitating the production of shorter A{beta} peptides and unveiling this specific region as a novel target for reducing the production of toxic A{beta} species.

neuroscience↗

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↗