Mutations in PS1 have been shown to cause early-onset inherited forms of Alzheimer's disease (AD) by a gain-of-function mechanism that alters proteolytic processing of the amyloid precursor protein (APP) resulting in increased production of neurotoxic forms of amyloid beta-peptide.
The rare familial mutations in APP and presenilin-1/2, which sometimes drive increased amyloid β (Aβ) production, may have unduly influenced Alzheimer's disease research.
In order to study the anti-inflammatory properties of ibuprofen independent of its anti-amyloidogenic activity, we performed a long-term treatment study with ibuprofen in 5XFAD mice expressing a presenilin-1 mutation that renders this AD model resistant to γ-secretase modulation.
The Alzheimer's Prevention Initiative Colombia Trial is a collaborative project involving the Neurosciences Group of Antioquia, Genentech/Roche, and the Banner Alzheimer's Institute, studying whether crenezumab can delay or prevent the clinical onset of Alzheimer's disease in cognitively unimpaired individuals who carry the <i>PSEN1 E280A</i> mutation.
Here, we studied the accumulation of Aβ, toxic turn Aβ and high-molecular-weight Aβ oligomers in presenilin 1 (PS1) gene-transfected SH-SY5Y cells as well as in the brains of 3xTg-AD mice and AD patients.
Although PSEN1 mutations are "deterministic" for Alzheimer's disease, they are associated with marked heterogeneity in the clinical expression of neurological features.
Moreover, blockade of gap junction hemichannel also significantly improved memory impairments without altering amyloid β deposition in double transgenic mice expressing human amyloid precursor protein with K595N and M596L mutations and presenilin 1 with A264E mutation as an Alzheimer's disease mouse model.
We report a presenilin-1 mutation (T245P) in a Japanese-American family with autosomal dominant Alzheimer's disease with an onset age in the early 40s.
The following observations suggest that such activity may play a similar role in humans with AD: (1) patients with sporadic AD have an increased incidence of seizures that appears to be independent of disease stage and highest in cases with early onset; (2) seizures are part of the natural history of many pedigrees with autosomal dominant early-onset AD, including those with mutations in presenilin-1, presenilin-2, or the amyloid precursor protein, or with duplications of wild-type amyloid precursor protein; (3) inheritance of the major known genetic risk factor for AD, apolipoprotein E4, is associated with subclinical epileptiform activity in carriers without dementia; and (4) some cases of episodic amnestic wandering and disorientation in AD are associated with epileptiform activity and can be prevented with antiepileptic drugs.
Recent studies suggest that mutations in the presenilin 1 gene, which encodes a polypeptide predicted to be a multispanning membrane protein, are responsible for the majority of cases of early onset, autosomal dominant Alzheimer's disease.
Enhanced accumulation of phosphorylated alpha-synuclein and elevated beta-amyloid 42/40 ratio caused by expression of the presenilin-1deltaT440 mutant associated with familial Lewy body disease and variant Alzheimer's disease.
Three causal genes have been identified in which mutations cause familial presenile AD: the amyloid precursor protein gene and the presenilin 1 and 2 genes.
Homozygosity for the 'T' allele of a polymorphism in the presenilin 1 gene has previously been reported to double the risk for Alzheimer's disease in a late onset Caucasian sample.
To model amyloid deposition in AD, we generated a new mouse line based on the presence of two copies of the genomic region encoding human wild-type AβPP as well as a mutation (L166P) in the murine Psen1.