To date, more than two hundred mutations distributed among almost a third of PS1's amino acids have been associated to the development of Alzheimer's disease (AD).
Excessive generation and accumulation of amyloid-β (Aβ) fragments by familial mutations of amyloid precursor protein (APP) and presenilin 1 (PS1) play a key role in causing oxidative stress, mitochondrial abnormalities and neuronal apoptosis in Alzheimer's disease (AD).
Our findings demonstrate how the structure of presenilin 1 dynamically changes during amyloid-β production, and provides insights toward the development of treatments against Alzheimer disease.
In this study, we set out to examine the link between the inflammatory, metabolic and iron-retentive signature of microglia in vitro and in transgenic mice that overexpress the amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1 mice), a commonly used animal model of AD.
Tissue-Specific Metabolomics Analysis Identifies the Liver as a Major Organ of Metabolic Disorders in Amyloid Precursor Protein/Presenilin 1 Mice of Alzheimer's Disease.
The results suggest that δ-catenin can influence the APP processing and its level by interacting with PS-1, which may eventually play a protective role in the degeneration of an Alzheimer's disease patient.
To address the impact of alcohol drinking on AD, studies were conducted using 3xTg-AD mice that express human MAPT, APP, and PSEN-1 transgenes and develop AD-like brain and behavioral pathology.
More than 200 distinct mutations in presenilin 1 (PSEN1) cause severe early-onset familial AD (FAD) and are thus of central interest to the etiology of AD.
Many mutations in the amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2) have been reported as the pathogenic causes of early-onset AD (EOAD), which accounts for up to 5% of all AD cases.
To understand the role of gangliosides in AD pathology in vivo, we crossed st3gal5-deficient (ST3<sup>-/-</sup>) mice that lack major brain gangliosides GM1, GD1a, GD3, GT1b, and GQ1b with 5XFAD transgenic mice that overexpress 3 mutant human amyloid proteins AP695 and 2 presenilin PS1 genes.
Three months later, LV-KL significantly induced Klotho overexpression in the brain and effectively ameliorated cognitive deficit and AD-like pathology in amyloid precursor protein/presenilin 1 mice.
Clinical case study and functional characterization of the disease-associated presenilin-1 (PSEN1) mutations may help reveal the roles of PSEN1 in the pathogenesis of Alzheimer's disease (AD).
We subjected double transgenic Alzheimer's disease (APP/PSEN1) and wild-type mice to mechanical ventilation for 4 h and compared to non-mechanically ventilated Alzheimer's disease model and wild-type mice.
We have previously showed that cellular cholesterol loading, by depleting the mitochondrial GSH (mGSH) content, stimulates Αβ-induced mitochondrial oxidative stress and promotes AD-like pathology in APP-PSEN1-SREBF2 mice.
To examine the role of sEH in pathogenesis of AD, we used wild-type (WT) mice, soluble epoxide hydrolase deficient (sEH<sup>-/-</sup>) and two mouse models of AD, including amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (APP/PS1 Tg) and APP/PS1 Tg/sEH<sup>-/-</sup> mice.
This was studied at two clinically translatable doses (2.5 and 5.0 mg/kg, BID), in a weight drop (concussive) mTBI model in wild type (WT) and AD APP/PSEN1 transgenic mice.
To investigate the basis for the hyperactivity, we performed electrophysiological and immunofluorescence studies on hiPSC-derived cerebrocortical neuronal cultures and cerebral organoids bearing AD-related mutations in presenilin-1 or amyloid precursor protein vs. isogenic gene corrected controls.
Previously, we found that total nitrosylated protein levels were increased in the brain of amyloid-β protein precursor (AβPP) and presenilin 1 (PS1) double transgenic mice, an animal model for AD, suggesting that cysteine oxidative protein modification may contribute to this disease.
Neuropathologic and molecular studies in brains of carriers of the PSEN1p.A396T mutation or other PSEN1 or PSEN2 mutations associated with the coexistence of DLBD and AD are needed to clarify whether tau and α-synuclein proteinopathies occur independently or whether a relationship exists between α-synuclein and tau that might explain the mechanisms of coaggregation.
The presenilin 1 and 2 conditional double knockout (PS cDKO) mice exhibit AD-like phenotypes including obvious neuroinflammatory responses and synaptic dysfunction and memory deficits.