**2. RNA splicing**

**1. Introduction**

4 Update on Dementia

neurons [2].

disorders [4].

loss [5].

[6].

cortex [7].

cases in 2050 is estimated to be 135 million [1].

Tau protein as the main component.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive loss of memory, orientation, sanity, and language. AD is a slow evolving disorder of multigenic nature with an average duration between 8 and 12 years. During the disease onset, symp‐ toms are overlooked generally for the first 2 or 3 years. There are few hereditary cases (genetic or familial AD) resulting from autosomal dominant inheritance of chromosomal alterations. This condition is the most common type of dementia, and it is globally recognized as one of the leading causes of morbidity and mortality among the advanced age population. In 2004, approximately 44 million cases of dementia were diagnosed worldwide and the number of

In AD, there is neuron loss and two typical alterations appear: the neuritic plaque produced by the β-amyloid (Aβ) and the neurofibrillary tangle that contains the hyperphosphorylated

Neuritic plaques are sphere-like structures in which the major component is the β-amyloid (Aβ) protein. The latter is generated by proteolytic cleavage of a larger protein, βAPP (Aβ precursor protein), and the neurofibrillar tangle, an intracellular damage affecting pyramidal

When the disease is diagnosed, its pathology has progressed several years [3]. Cerebral changes underlying AD probably develop 20–30 years before the first symptoms appear.

AD diagnosis combines psychological and imaging tests as well as the exclusion of neurologic

The pathological processes frequently linked to AD are as follows: aging, amyloid deposition, neurofibrillar degeneration, synaptic loss, inflammation, loss of vascular integrity, and neuron

The development of tangles and plaques leads to neuron death. Tangles are mainly located at the entorhinal cortex, hippocampus, parahippocampal gyrus, amygdala, and frontal, tempo‐ ral, parietal, and occipital cortices and some subcortical nuclei projected toward these regions

Tangles are composed by paired helical filaments (PHF), in which the latter are gathered in helixes. Neuritic plaques are microscopic foci of extracellular amyloid depositions associated with axon and neurite damage. They are found in large amounts at the limbic and association

At the neuritic plaques, it is observed an abnormal extracellular accumulation of the Aβ peptide, comprised by 40 or 42 amino acids (Aβ40 and Aβ42) [8]. Dystrophic neurites are located both within and surrounding the amyloid depositions, and they are distinguished by

These plaques are associated with microglia either contiguous or within the amyloid nucleus. The period of time for neuritic plaque development is unknown. Most of the fibrillar Aβ located

structural abnormalities including lysosomes, mitochondria, and PHF.

Ribonucleic acid (RNA) splicing is a mechanism used by eukaryotic cells in order to eliminate introns. These introns are non-coding RNA sequences, and therefore, they need to be removed by a ribonucleoprotein-rich structure termed the spliceosome complex. Thus, exon sequences are joined, producing a mature transcript that is available for migrating from the cell nucleus to the cytoplasm in order to be translated into a protein.

Splicing mechanism must be very accurate, as at least 50% of human genetic diseases are associated with mutations occurring in consensus sequences of splicing sites. These sequences consist on GU at the 5′ intron and an AG sequence at 3′. Toward the 5′ end of the intron, there is a pyrimidine-rich region (C U).

In order to carry out the splicing, the spliceosome complex needs to be assembled. The consensus sequences located at the exon–intron boundary are essential to bind the 5 ribonu‐ cleoproteins (snRNP) U1, U2, U4, U5, and U6 in such sequences in order to form the spliceo‐ some. Several protein complexes constitute the spliceosome: the complex E (U1 binds to the GU sequence at the 5′ site of an intron, SF1 binds to the intron branch point, U2AF1 binds to the 3′ splicing site, and U2F2 binds to the polypirimidine sequence), the complex A (U2 displaces SF1 and it binds to the branch point sequence), the complex B (U5, U4, and U6 form a trimer that bind to U2 along with U5). U1 is released, U5 shifts from exon to intron, and U6 binds to the 5′ splicing site). Complex C (U4 is released, and U6/U2 catalyze a transesterification to induce the binding of the 5′-end intron to the complex A, forming an intron lariat. U5 bind to the exon 3′ splicing site, which is cleaved). Afterward, U2, U5, and U6 remain bound to the lariat forms and the 3′ site is cleaved, whereas exons are ligated by means of ATP hydrolysis. Lariat forms are degraded, and the snRNP are recycled (**Figure 1**).

Alternative splicing generally is a mean by which a gene may generate a variety of messen‐ ger RNAs (mRNAs) with biological significance, that is coding for a protein. It has been estimated that at least 90% of all expressed genes are subjected to alternative splicing.

It has been identified at least six ways to generate alternative splicing: (a) exon exclusion or inclusion, (b) selecting one or more exons, (c) and (d) competition for the splicing site at a defined exon either in the 5′ or 3′ region, (e) retaining an intron, (f) multiple promoters, (g) multiple poly-A sites [12] (**Figure 2**). Exon and intron sequences may regulate the splicing site through enhancer or silencer sequences.

**Figure 1.** RNA splicing. Exon 1 flanked on its 3′ end by the GU sequence and exon 2 on its 5′ end by AG, with both target sites for the ribonucleoproteins and the assembled spliceosome complex. The spliceosome will cut the intron in the consensus sequences and will enable the joining of the exons, generating a mature RNA. Scheme taken from [49].

**Figure 2.** Forms of alternative splicing. (**A**) Exclusion or inclusion of exons, (**B**) selection of one or more exons, (**C**) in‐ tron retention, (**D**) competencies by the site of splicing in a particular exon in the region 5′ or 3′, (**E**) multiple promot‐ ers, (**F**) multiple poly-A sites.
