Scientific Report12 November 2015Open Access ApoE4 upregulates the activity of mitochondria-associated ER membranes Marc D Tambini Integrated Program in Cellular, Molecular and Biomedical Studies, Columbia University Medical Center, New York, NY, USA Search for more papers by this author Marta Pera Department Neurology, Ellen Kanter Hua Yang Cristina Guardia-Laguarta Pathology Cell Biology, David Holtzman Hope Center Neurological Disorders, Knight Alzheimer's Disease Research Washington...

To study the mechanisms by which p.R47H variant of microglia gene and Alzheimer's disease (AD) risk factor TREM2 increases dementia risk, we created Trem2R47H KI rats. rats were engineered to produce human Aβ define human-Aβ-dependent -independent pathogenic triggered this variant. Interestingly, pre- peri-adolescent present increased brain concentrations TNF-α, augmented glutamatergic transmission, suppression Long-term-Potentiation (LTP), an electrophysiological surrogate learning memory,...

Cleavage of APP by BACE1/β-secretase initiates the amyloidogenic cascade leading to Amyloid-β (Aβ) production. α-Secretase non-amyloidogenic pathway preventing Aβ Several mutations cause familial Alzheimer’s disease (AD), while Icelandic mutation near BACE1-cleavage site protects from sporadic dementia, emphasizing APP’s role in dementia pathogenesis. To study protective/pathogenic mechanisms, we generated knock-in rats carrying either protective (Appp) or pathogenic Swedish (Apps), also...

Abstract Amyloid precursor protein ( APP ) modulates glutamate release via cytoplasmic and intravesicular interactions with the synaptic vesicle machinery. The domain, called ISVAID , contains BACE 1 cleavage site of . We have tested functional significance processing using App ‐Swedish s knock‐in rats, which carry an mutation that causes familial Alzheimer's disease FAD in humans. show β‐cleavage is favored over α‐cleavage. rats facilitated glutamate, but not GABA release. Our data support...

Abstract Mutations in the Integral membrane protein 2B ( ITM2b/BRI2 ) gene, which codes for a called BRI2, cause familial British and Danish dementia (FBD FDD). Loss of BRI2 function and/or accumulation amyloidogenic mutant BRI2-derived peptides have been proposed to mediate FDD FBD pathogenesis by impairing synaptic Long-term potentiation (LTP). However, precise site nature dysfunction remain unknown. Here we use genetic approach inactivate Itm2b either presynaptic (CA3), postsynaptic (CA1)...

Familial forms of Alzheimer's disease (FAD) are caused by mutations in the gene encoding amyloid precursor protein, whose processing can result formation β-amyloid (Aβ). FAD also from presenilin 1/2 (PSEN1/2) genes, protein products partially compose γ-secretase complex that cleaves Aβ fragments. Psen1 KO mice and knock-in (KI) with homozygous FAD-associated L435F (Psen1LF/LF) embryonic perinatally lethal, precluding a more rigorous examination effect disease–causing on neurodegeneration....

The Amyloid Precursor Protein (APP), a genetic cause of Alzheimer's disease (AD), is type-I transmembrane protein that metabolized by proteolysis in the endolysomal system. APP and its metabolites are secreted cells extracellular vesicles (EVs). To study function APP-containing EVs, we isolated App-EVs from rat primary neuronal conditioned media proteomic analysis identified Valosin-containing (Vcp) as molecular cargo. Pharmacological modulation Vcp activity was found to alter App processing...

Abstract TAU mutations are genetically linked to fronto-temporal dementia (FTD) and hyper-phosphorylated aggregates of Tau form neurofibrillary tangles (NFTs) that constitute a pathological hallmark Alzheimer disease (AD) FTD. These observations indicate has pivotal role in the pathogenesis neurodegenerative disorders. is cleaved by caspases at Aspartate 421 , metabolite known as δTau; δTau increased AD, due hyper-activation AD brains. considered critical toxic moiety underlying...

APP, whose mutations cause familial Alzheimer9s disease (FAD), modulates neurotransmission via interaction of its cytoplasmic tail with the synaptic release machinery. Here we identified an intravesicular domain called intraluminal SV-APP interacting (ISVAID), which interacts glutamatergic, but not GABAergic, vesicle proteins. ISVAID contains β- and α-secretase cleavage sites APP: proteomic analysis interactome suggests that APP cuts inside destabilizes protein–protein interactions. We have...

Abstract The R47H variant of the Triggering-Receptor-Expressed on Myeloid cells 2 (TREM2) increases risk Alzheimer’s disease (AD). Mutagenesis exon in Knock-in (KI) mouse models introduced a cryptic splice site, leading to nonsense mediated decay. Since haploinsufficiency does not model Trem2-R47H function, new rat KI model, Trem2 was created. Human Aβ has higher propensity form toxic species, which are considered main pathogenic entity AD, as compared rodent Aβ, Amyloid Precursor Protein (...

About 2% of Alzheimer's disease (AD) cases have early onset (FAD) and are caused by mutations in either Presenilins (PSEN1/2) or amyloid-β precursor protein (APP). PSEN1/2 catalyze production Aβ peptides different length from APP. the major components amyloid plaques, a pathological lesion that characterizes AD. Analysis mechanisms which APP affect peptide compositions lead to implication absolute relative increase Aβ42 plaques formation. Here, elucidate formation pathogenic cocktails...

Cleavage of Amyloid precursor protein by β- and γ-secretases lead to Aβ formation. The widely accepted pathogenic model states that these mutations cause AD via an increase in formation accumulation plaques. APP early onset familial forms Alzheimer’s disease (FAD) humans. We generated App −Swedish ( s ) knock−in rats, which carry a mutation the endogenous rat gene. This increases β-secretase processing leading both augmented production facilitation glutamate release s/s APP−dependent...

<title>Abstract</title> APOE is a major genetic factor in late-onset Alzheimer's disease (LOAD), with APOE4 significantly increasing risk, APOE3 acting as neutral isoform, and APOE2 offering protective effects. The primary hypothesis links isoforms to LOAD through their impact on Aβ production deposition, which thought be related effects lipid metabolism. Specifically, enhances accumulation amyloid plaques more than APOE3. In contrast, APOE3-Aβ complexes, promote clearance reduce...

Abstract The Amyloid Precursor Protein (APP) undergoes extensive proteolytic processing to produce several biologically active metabolites which affect Alzheimer’s disease (AD) pathogenesis. Sequential cleavage of APP by β- and γ-secretases results in Aβ, while α- produces the smaller p3 peptide. Here we report that cells P4-ATPase flippase subunit CDC50A has been knocked out, large increases products α-secretase (sAPPβ/βCTF sAPPα/αCTF, respectively) downstream Aβ are seen. These data...