**6. Conclusion**

APP751 is expressed in all tissues and it includes exon 7, codifying a domain similar to that of

In neurons, APP is found on terminal vesicles in axons and it can be transported in an anterograde or retrograde manner [38]. Other brain cells also express APP and release variable

APP may be subjected to protelytic cleavage during and after its transit through the secretory pathway. The first of them is carried out by the α-secretase enzyme resulting in the release of a large and soluble ectodomain fragment (α-APP) [39] in the extracellular space, while retaining a 83-residue C-terminal fragment (CTF) in the membrane. Alternatively, some APP molecules that were not cleaved by α-secretase may be processed by the activity of an enzyme named β-secretase, generating a β-APP ectodomain that retains one residue from the 99 CTF

The main β-secretase in neurons is a transmembrane aspartyl protease named BACE1, predominantly located at the transgolgi network (TGN) and also in endosomes [40]. The cleavage mediated by BACE1 generates the N-terminal fragment of Aβ. The high level of neuronal BACE1 expression preferably targets APP to the amyloidogenic processing pathway in the brain [34]. Aβ is constitutively released from cells expressing APP in normal conditions. The cleavage generated by β-secretase is followed by a constitutive trim at the C-terminal of the Aβ region, and it is carried out by the activity of γ-secretase. Simultaneously, a peptide fragment designated as p3 is produced from the sequential activity of both α- and γ-secretases [6]. A substantial amount of α-APP is generated by γ-secretase that acts on the inserted APP

The Aβ40 and Aβ42 fragments are generated to a large extent during APP internalization and endosomal processing. Most of the Aβ generated within the cell is destined for secretion.

APP has autocrine and paracrine functions during growth regulation. It has been best characterized as trophic as it has been demonstrated that it stimulates neurite growth. This phenotype is compatible with its increased expression during neuron maturation [41, 42].

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

the Kunitz protease inhibitor [37].

10 Update on Dementia

[6].

in plasma membrane.

**5. PSEN 1 and PSEN 2**

amounts of Aβ, including astrocytes and microglia.

Currently, there is no cure for Alzheimer's disease and the research conducted nowadays in order to fully understand this condition is relevant. Nevertheless, its underlying causes have not yet been determined.

The mechanism of the disease is not fully understood, and the conducted studies have shown that proteins such as Tau, APP, and both presenilins are highly important for developing the disease.

Through artificial intelligence studies, it has been demonstrated that more than 70 genes are associated to these proteins [48], rendering this disease extremely complex.

Alternative splicing is key in order to generate the appropriate proteins that do not affect neuron functioning; thus, the individual may carry a healthy life.
