Aβ −42 deposition precedes other changes in PS-1 Alzheimer's disease

Abstract

The sequence of events which result in β-amyloid (Aβ) plaques and tau-rich neurofibrillary tangles (NFT) in the tau-rich brain, the signature lesions of Alzheimer's disease, are incompletely understood. We know that metabolic breakdown of the amyloid precursor protein (APP) within the endoplasmic reticulum and the Golgi apparatus results in formation of different length Aβ peptides (Aβ−42 and the shorter Aβ−40). 1 Cook DG Forman MS Sung JC et al. Alzheimer's Aβ(1–42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nat Med. 1997; 3: 1021-1023 Crossref PubMed Scopus (426) Google Scholar Because elderly people with Down's syndrome develop Alzheimer's disease, the occurrence of Aβ−42 plaques before other changes in trisomy 21 2 Iwatsubo T Mann DMA Odaka et al. Amyloid β protein (Aβ) deposition: Aβ42(43) precedes Aβ40 in Down syndrome. Ann Neurol. 1995; 37: 294-299 Crossref PubMed Scopus (335) Google Scholar suggests that Aβ−42 deposition is the earliest event in Alzheimer's disease. Aβ−42 and Aβ−40 are present in older people with Down's syndrome and in Alzheimer's disease. 2 Iwatsubo T Mann DMA Odaka et al. Amyloid β protein (Aβ) deposition: Aβ42(43) precedes Aβ40 in Down syndrome. Ann Neurol. 1995; 37: 294-299 Crossref PubMed Scopus (335) Google Scholar However, in trisomy 21 there is an extra copy of the APP gene with overexpression of APP, so the early occurence of Aβ cannot be generalised to all people with Alzheimer's disease. To define the initial pathological features in Alzheimer's disease due to genetic abnormalities that do not involve the APP gene we report here the neuropathology of a presymptomatic carrier of the FAD1 presenilin-1 (PS-1) Alzheimer-disease mutation on chromosome 14. 3 Nee LE Polinsky RJ Eldridge R et al. A family with histologically confirmed Alzheimer's disease. Arch Neurol. 1983; 40: 203-208 Crossref PubMed Scopus (135) Google Scholar This mutation causes the disease in all carriers with an average age of onset of dementia at 53 and of death at 61. Because PS-1 is a transmembrane protein located in the Golgi apparatus and endoplasmic reticulum, PS-1 mutations may cause Alzheimer's disease by an interaction with the APP protein in these sites.