Aβ42, Presenilins, and Alzheimer’s Disease

doi:10.1016/S0197-4580(98)00027-X

Neurobiology of Aging

Volume 19, Issue 1, Supplement 1, January–February 1998, Pages S11-S13

https://doi.org/10.1016/S0197-4580(98)00027-X Get rights and content

Abstract

The significance of amyloid β protein, especially those ending at the 42nd residue (Aβ42), in the pathogenesis of familial Alzheimer’s disease (FAD) linked to the mutations of presenilins, was examined by transfection studies using cultured cells and immunohistochemical analysis of autopsied brains. The levels of Aβ42 secreted from cells transfected with mutant presenilins linked to FAD, as well as the Aβ42 burden in the cortices of patients with presenilin mutation were elevated. Thus, mutations in presenilin genes may enhance the production and deposition of Aβ42 in the brains, thereby leading to Alzheimer’s disease.

Section snippets

Materials and Methods

COS-1 cells were transfected with cDNAs encoding wild-type or N141I mutant PS2 together with human APP cDNAs. Mouse neuroblastoma neuro2a (N2a) cells were transfected with wild-type or N141I mutant PS3 cDNAs, and cells stably expressing these cDNAs were cloned. The levels of Aβ40 and Aβ42 secreted from these cells were quantitated by two-site ELISAs as described [13].

Sections from formalin-fixed, paraffin embedded frontal cortices from eight cases of FAD with five different PS1 mutations [8]and

Results and Discussion

The mean level ± S.E. of Aβx-42 secreted from COS cells transiently transfected with N141I mutant PS2 and βAPP cDNAs was 53.2 ± 6.7 pM (n = 3), which was 1.8-fold compared with that from cells with wild-type PS2 (29.6 ± 1.7 pM). The mean level ± S.E. of Aβ42 secreted from three independent N2a cell lines stably expressing N141I mutant PS2 was 262.9 ± 14.9 pM (n = 4 per each clone), which were ∼8 times higher than those in cells with wild-type PS2 (33.6 ± 3.6 pM).

The density and percentage area

Acknowledgements

The author thanks Drs. Kei Maruyama, Taisuke Tomita, Takaomi C. Saido, David M.A. Mann and all other collaborators for their significant contributions to this study. Especially, the molecular biological studies of presenilins were conducted under the direction of K.M. at the Laboratory of Neurochemistry, National Institute for Physiological Sciences, Japan, as well as in the University of Tokyo.

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Cited by (11)

Presenilins and Alzheimer's disease: Biological functions and pathogenic mechanisms
2000, Progress in Neurobiology
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly population. Dementia is associated with massive accumulation of fibrillary aggregates in various cortical and subcortical regions of the brain. These aggregates appear intracellularly as neurofibrillary tangles, extracellularly as amyloid plaques and perivascular amyloid in cerebral blood vessels. The causative factors in AD etiology implicate both, genetic and environmental factors. The large majority of early-onset familial Alzheimer’s disease (FAD) cases are linked to mutations in the genes coding for presenilin 1 (PS1) and presenilin 2 (PS2). The corresponding proteins are 467 (PS1) and 448 (PS2) amino-acids long, respectively. Both are membrane proteins with multiple transmembrane regions. Presenilins show a high degree of conservation between species and a presenilin homologue with definite conservation of the hydrophobic structure has been identified even in the plant Arabidopsis thaliana. More than 50 missense mutations in PS1 and two missense mutations in PS2 were identified which are causative for FAD. PS mutations lead to the same functional consequence as mutations on amyloid precursor protein (APP), altering the processing of APP towards the release of the more amyloidogenic form 1–42 of Aβ (Aβ42). In this regard, the physical interaction between APP and presenilins in the endoplasmic reticulum has been demonstrated and might play a key role in Aβ42 production. It was hypothesized that PS1 might directly cleave APP. However, extracellular amyloidogenesis and Aβ production might not be the sole factor involved in AD pathology and several lines of evidence support a role of apoptosis in the massive neuronal loss observed. Presenilins were shown to modify the apoptotic response in several cellular systems including primary neuronal cultures. Some evidence is accumulating which points towards the β-catenin signaling pathways to be causally involved in presenilin mediated cell death. Increased degradation of β-catenin has been shown in brain of AD patients with PS1 mutations and reduced β-catenin signaling increased neuronal vulnerability to apoptosis in cell culture models. The study of presenilin physiological functions and the pathological mechanisms underlying their role in pathogenesis clearly advanced our understanding of cellular mechanisms underlying the neuronal cell death and will contribute to the identification of novel drug targets for the treatment of AD.
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Original ArticlesAβ42, Presenilins, and Alzheimer’s Disease

Abstract

Section snippets

Materials and Methods

Results and Discussion

Acknowledgements

Neuron

Biochem. Biophys. Res. Comm.

Alzheimer Aβ(1–42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells

Nature Med.

Amyloid β protein deposition in normal aging has the same characteristics as that in Alzheimer’s disease. Predominance of Aβ42(43) and association of Aβ40 with cored plaques

Am. J. Pathol.

Amyloid β protein (Aβ) deposition. Aβ42(43) precedes Aβ40 in Down syndrome

Ann. Neurol.

Full-length amyloid-β(1–42(43)) as well as amino-terminally modified and truncated amyloid-β42(43) deposit in diffuse plaques

Am. J. Pathol.

Original Articles
Aβ42, Presenilins, and Alzheimer’s Disease