**5. PSEN 1 and PSEN 2**

Presenilins (PSEN) are an important part of the γ-secretase enzyme activity, and they are responsible for the proteolytic cleavage of APP. γ-secretase is a multimeric complex of PSEN1 or PSEN2, nicastrin, and APH1. All mutations in PSEN1 increase APP cleaving activity by γsecretase, which generates the Aβ42 fragment. The PSEN1 gene is located in chromosome 14 and that of PSEN2 in chromosome 1, both of them are approximately 60% similar [43]. Regarding the gene's structure, it has been demonstrated that the first 4 exons contain untranslated regions, and exons 1 and 2 possess alternative transcription sites. The function of these sites is still unclear. The first ATG is located in exon 4, and its 12 bp is used as an alternative splicing donor site. Exon 9 is subjected to alternative splicing in leukocytes but not in other tissues. Most of the expressed transcripts are polyadenylated after the TAG stop codon in exon 13 [44]. A PSEN 2 variant has been shown to lack exon 5, which has been detected on individuals with sporadic Alzheimer's disease [45].

Several mutations on the PSEN genes are responsible for early familial Alzheimer's disease. The loss of exons 3 and 4 of PSEN demonstrates that transcripts are efficiently translated as truncated proteins at their N-terminal; however, this does not affect their function as amyloid fragment generators [46].

A PSEN2 variant that does not possess exon 5 has been reported to increase the generation of the Aβ40 y 42 fragments [47].
