**9. Presenilins 1 and 2**

Presenilins (PSs) are membrane proteins encoded by two genes: PS1 and PS2. PS, nicastrin, anterior pharynx-defective (aph-1) and presenilin enhancer 2 (pen-2) form an active part of the γ-secretase complex, while PS form the catalytic core of the complex [18].

Presenilin-1 (PS1) and presenilin-2 (PS2) are considered as the key elements of the γ-secretase complex. The proteins are composed of 9 transmembrane domains containing 467 or 448 amino acids. These domains are autoproteolytically cleaved in the process endoproteolysis to form two ends, each of them having an active aspartate site, which create the catalytic γ-secretase complex site for Aβ. Anterior pharynx-defective (Aph-1) and presenilin enhancer 2 (Pen-2) act as cofactors in the active γ-secretase complex. Aph-1 is a transmembrane protein composed of seven subunits with *N*- and *C-*ends protruding into the lumen and the cytosol. It plays an important role in the initial formation of γ-secretase and carries out the enzymatic function in the final complex. Pen-2 is the smallest membrane protein with two transmembrane domains, in which both the *C*- and *N*-ends point to the lumen. Pen-2 holds an important role in stabilizing PS in the final step of γ-secretase building and also helps in endoproteolysis of presenilins [37].

**10. Apolipoprotein E and other apolipoproteins**

distortion of memory functions and increased levels of *APOE-ε4* [41].

**11. Aβ and neurodegeneration**

lary tangles and induce the death of neurons [42].

**12. Conclusion**

Apolipoprotein (APO) is a general term for denoting proteins which bind with lipids. They play an important role in the regulation of pathological manifestations caused by Aβ. APOE is the main representative of the APO present in the CNS, which is produced and secreted exclusively by astrocytes and microglia. APOE is involved in the transport of lipids between the cells in the CNS, where it physiologically induces the lipid homeostasis, repairs damaged neurons, supports synaptic transmission of excitation and separates specific toxins. The *APOE* gene is encoded by three alleles—*APO-ε2, APO-ε3* and *APOE-ε4*. These alleles differ in only two residues at positions 112 and 158. These small differences between the alleles, however, determine their different function. The isoform *APOE-ε2* carries out a neuroprotective function, while the isoform *APOE-ε4*, occurring in a population at about 14%, is associated with a number of diseases. Many studies point to the *APOE-ε4* allele as a risk factor associated with cognitive dysfunction and the onset of AD. The effect of *APOE-ε4* is regulated by cholesterol. The *APOE-ε4* variant has a function of chaperone in relation to the Aβ. The chaperone assists in structural formation of Aβ, but, in fact, it also increases the toxicity of Aβ. The consequences of the relation of *APOE-ε4* to Aβ were demonstrated on transgenic animals, when blocking the interaction of *APOE-ε4* with Aβ significantly reduced the accumulation of Aβ into amyloid deposits. The deposition degree of Aβ depends on the presence of the APOE alleles and descends in a series of *APOE-ε4* > *APOE-ε3* > *APOE-ε2*. Interestingly, the intake of sugary drinks leads to induction of the amyloidogenic process, to

Amyloid Beta Hypothesis: Attention to β- and γ-Secretase Modulators

http://dx.doi.org/10.5772/intechopen.75629

13

A number of studies show that Aβ plays a key role in the onset and progression of AD. But so far, it is still not clear whether the culprit of the onset of dementia is the soluble or insoluble form of Aβ and if the extent of the Aβ impact depends on the localization of this protein in extracellular or intracellular compartments. Current research has revealed a variety of processes in which Aβ plays an important role, for instance, mitochondrial dysfunction, oxidative stress, turmoil and disruption of the transfer function of the membrane. According to the amyloid hypothesis, deposition of Aβ in the brain is the primary cause and controlling force of the degeneration associated with AD, which involves formation of intracellular neurofibril-

AD is a complex neurodegenerative disease which is caused by a number of factors, both biological and environmental. Among these factors, one of the main elements is excessive production of Aβ via amyloidogenic processing of APP, and its subsequent storage in the brain. All of these processes lead to neuronal death, which initializes the outbreak

Nicastrin has been described as the main protein that interacts with presenilins. This part of the γ-secretase complex contains 709 amino acids including glycoprotein with 1 large ektodomain and can serve as the substrate receptor of γ-secretase. Nicastrin is essential for the recognition and processing of the substrate, for the maturation of the γ-secretase complex and its transport to the cell surface [38].

In addition to the amyloidogenic fragment of APP (i.e., sAPPβ), γ-secretase breaks down also a variety of other transmembrane proteins (e.g. Notch). Mutation in PS1 often leads to an increase in the relative production of toxic Aβ1–42 peptide, which is hydrophobic and is easily prone to aggregation. This process results in a cascade of pathological events, at the end of which a degenerative damage to neurons comes up. The hypothesis about the influence of PS1 mutations on the creation and subsequent aggregation of Aβ1–42 was supported by the results of studies on transgenic mice with an increased production of APP, in which increased formation and accelerated storage of the Aβ deposits occurred. Moreover, the PS mutations always appear in different parts of the protein, so it can be hard to predict what toxic effect due to PS mutation will show up. In this context, however, it is possible that the loss of normal functions of the PS caused by one of the mutations closely correlates with the onset of pathological cascades leading to AD.

The most recent studies have pointed to the loss of function of PS, which is usually associated with the mechanism of AD development. In this respect, it was proved that mice with the knockout genes for both PS proteins exhibit degenerative disruption of the front part of the brain, without the formation and storage of Aβ, although cognitive dysfunctions arise as it is normally observed in AD with the appearance of Aβ in the brain. Similar symptoms can be found in frontotemporal dementia in humans, which is presumably caused by a mutation of the gene for PS1, when amyloidogenesis (i.e., formation of Aβ) does not occur. From the abovementioned information, it follows that neurodegeneration may proceed even without the formation of Aβ [39].

However, PS also plays an important role in many other physiological processes. These processes can be divided into those related with the activity of γ-secretase and those without a close connection with the activity of γ-secretase. It is interesting that some of the inhibitors of γ-secretase increase the production of Aβ1–42 in low concentrations while reducing the formation of Aβ1–40. A similar effect can be observed as a result of PS mutations [40].
