The varied ways in which mutations in presenilins (PSEN1 and PSEN2) affect amyloid b precursor protein (APP) processing in causing early-onset familial Alzheimer disease (FAD) are complex and not yet properly understood. Nonetheless, one useful diagnostic marker is an increased ratio of Ab42 to Ab40 (Ab42/Ab40) in patients' brain and biological fluids as well as in transgenic mice and cells. We studied Ab and APP processing for a set of nine clinical PSEN mutations on a novel and highly reproducible enzyme-linked immunosorbent assay (ELISA)-based in vitro method and also sought correlation with brain Ab analyzed by image densitometry and mass spectrometry. All mutations significantly increased Ab42/Ab40 in vitro by significantly decreasing Ab40 with accumulation of APP C-terminal fragments, a sign of decreased PSEN activity. A significant increase in absolute levels of Ab42 was observed for only half of the mutations tested. We also showed that age-of-onset of PSEN1-linked FAD correlated inversely with Ab42/Ab40 (r=–0.89; P=0.001) and absolute levels of Ab42 (r=–0.83; P=0.006), but directly with Ab40 levels (r=0.69; P=0.035). These changes also partly correlated with brain Ab42 and Ab40 levels. Together, our data suggested that Ab40 might be protective by perhaps sequestering the more toxic Ab42 and facilitating its clearance. Also, the in vitro method we describe here is a valid tool for assaying the pathogenic potential of clinical PSEN mutations in a molecular diagnostic setting. Hum Mutat 27(7), 686–695, 2006. Published 2006 Wiley-Liss, Inc.

Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Aβ42 and decreased Aβ40†‡§

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the growing population of elderly people. A hallmark of AD is the accumulation of plaques in the brain of AD patients. The p

Amyloid-beta aggregation.

Alzheimer's disease (AD) is a complex disorder of the central nervous system (CNS). Molecular genetic research has provided a wealth of information regarding the genetic etiology of this devastating disease. Identification and functional characterization of autosomal dominant mutations in the amyloid precursor protein gene (APP) and the presenilin genes 1 and 2 (PSEN1 and PSEN2) have contributed substantially to our understanding of the biological mechanisms leading towards CNS neurodegeneration in AD. Nonetheless, a large part of the genetic etiology remains unresolved, especially that of more common, sporadic forms of AD. While substantial efforts were invested in the identification of genetic risk factors underlying sporadic AD, using carefully designed genetic association studies in large patient-control groups, the only firmly established risk factor remains the epsilon4 allele of the apolipoprotein E gene (APOE). Nevertheless, one can expect that with the current availability of high-throughput genotyping platforms and dense maps of single-nucleotide polymorphisms (SNPs), large-scale genetic studies will eventually generate additional knowledge about the genetic risk profile for AD. This review provides an overview of the current understanding in the field of AD genetics, covering both the rare monogenic forms as well as recent developments in the search for novel AD susceptibility genes.

https://www.tandfonline.com/doi/pdf/10.1080/07853890802186905

Molecular genetics of Alzheimer's disease: an update.

Familial forms of frontotemporal dementia (FTD) with tauopathy are mostly caused by mutations in the gene encoding the microtubule-associated protein tau (MAPT). However, rare forms of familial tauopathy without MAPT mutations have been reported, suggesting other tauopathy-related genetic defects. Interestingly, two presenilin 1 (PS1) mutations (Leu113Pro and insArg352) recently have been associated with familial FTD albeit without neuropathological confirmation. We report here a novel PS1 mutation in a patient with Pick-type tauopathy in the absence of extracellular beta-amyloid deposits. The mutation is predicted to substitute Gly-->Val at codon position 183 (Gly183Val) and to affect the splice signal at the junction of the sixth exon and intron. Further clinical-genetic investigation showed a positive family history of FTD-like dementia and suggested that Gly183Val is associated with a phenotypically heterogeneous neurodegenerative disorder. Our results suggest PS1 as a candidate gene for Pick-type tauopathy without MAPT mutations.

A novel presenilin 1 mutation associated with Pick's disease but not beta-amyloid plaques.

Tumor necrosis factor type I receptor (TNFRI), a death receptor, mediates apoptosis and plays a crucial role in the interaction between the nervous and immune systems. A direct link between death receptor activation and signal cascade-mediated neuron death in brains with neurodegenerative disorders remains inconclusive. Here, we show that amyloid-β protein (Aβ), a major component of plaques in the Alzheimer's diseased brain, induces neuronal apoptosis through TNFRI by using primary neurons overexpressing TNFRI by viral infection or neurons from TNFRI knock-out mice. This was mediated via alteration of apoptotic protease-activating factor (Apaf-1) expression that in turn induced activation of nuclear factor κB (NF-κB). Aβ-induced neuronal apoptosis was reduced with lower Apaf-1 expression, and little NF-κB activation was found in the neurons with mutated Apaf-1 or a deletion of TNFRI compared with the cells from wild-type (WT) mice. Our studies suggest a novel neuronal response of Aβ, which occurs through a TNF receptor signaling cascade and a caspase-dependent death pathway.

https://www.jneurosci.org/content/jneuro/24/7/1760.full.pdf

Tumor Necrosis Factor Death Receptor Signaling Cascade Is Required for Amyloid-β Protein-Induced Neuron Death

In vitro studies of Flemish, Dutch, and wild-type beta-amyloid provide evidence for two-staged neurotoxicity.

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In vitro studies of Flemish, Dutch, and wild-type beta-amyloid provide evidence for two-staged neurotoxicity.