Early onset Alzheimer's disease and oxidative stress

Abstract

Alzheimer's disease (AD) is the most common cause of dementia in elderly adults. It is estimated that 10% of the world's population aged more than 60-65 years could currently be affected by AD, and that in the next 20 years, there could be more than 30 million people affected by this pathology. One of the great challenges in this regard is that AD is not just a scientific problem; it is associated with major psychosocial and ethical dilemmas and has a negative impact on national economies. The neurodegenerative process that occurs in AD involves a specific nervous cell dysfunction, which leads to neuronal death. Mutations in APP, PS1, and PS2 genes are causes for early onset AD. Several animal models have demonstrated that alterations in these proteins are able to induce oxidative damage, which in turn favors the development of AD. This paper provides a review of many, although not all, of the mutations present in patients with familial Alzheimer's disease and the association between some of these mutations with both oxidative damage and the development of the pathology.

Figure 1

APPβ processing. the APP is an integral membrane protein and is sequentially processed by the three proteases α-, β-, and γ-secretase. The nonamyloidogenic pathway involves the α-secretase, which made the cut at the middle portion of the fragment corresponding to the amyloid sequence, preventing the amyloid peptides generation. The amyloidogenic pathway involves β-secretase, leading to the formation of C-terminal fragments (CTFs) that are subsequently cleaved by the “γ-secretase-complex” which is responsible for the formation of Aβ (40 or 42 amino acids in length) and the AβPP intracellular domain peptide (AICD) of 58 or 56 amino acids.

Figure 2

Human APP gene structure. (a) The APP gene consisting of 18 exons is located on chromosome 21 (21q21.2-3) and is alternatively spliced into several products, named according to their length in amino acids (i.e., APP695, APP714, APP751, APP770, and APP563) that are expressed differentially by tissue type. The region encoding the amyloid sequence comprises part of exons 16 and 17 (red box). (b) APP is a member of a family of conserved type I membrane proteins and consists of a large extracellular domain, a hydrophobic transmembrane domain, and a short cytoplasmic carboxyl terminus. Some isoforms contain a domain homologous to the Kunitz-type serine protease inhibitors (KPI) in the extracellular sequences (pink box). Amyloid sequence contains 40- and 43-amino-acid residues that extend from the ectodomain into the transmembrane domain of the protein. The Aβ sequence lies partially outside the cell membrane (amino acids 1–17 of Aβ) and the some identified mutations in the protein are indicated in bold.

Figure 3

Schematic representation of Presenilin 1. Presenilins are membrane proteins that form the catalytic core of the γ-secretase complex. The PSEN1 gene is located on chromosome 14q24.2 and comprises 12 exons. PS1 is an integral membrane protein with eight transmembrane domains and a hydrophilic domain between domains 6 and 7. Two aspartate residues in transmembrane domains, (TMs) 6 and 7 constituting the catalytic site. To date, more than 185 mutations in PSEN1 have been described in 405 families all of which are related to the appearance of the disease at younger ages. Although mutations are found throughout the protein, most are located in the transmembrane region.

Figure 4

Schematic representation of Presenilin 1. The PSEN2 gene is located on chromosome 1q42.13 and comprises 12 exons, of which only 10 are translated to generate a protein with a length of 448 amino acid residues. This protein exhibits 9 transmembrane domains and displays tissue-specific alternative splicing; major mutations found in the protein are identified.