Preface

The progress of medicine and technology in the second half of the twentieth century has led to an increase in life expectancy. This phenomenon was accompanied by a higher incidence of diseases typical for old age, including Alzheimer's disease. It is known that the incidence of Alzheimer's disease is largely dependent on the patient's age. Alzheimer's disease is cur‐ rently considered an incurable disease with an incomplete etiology and comprises a serious social and economic problem for many countries.

Nowadays, Alzheimer's disease is considered to be the most common dementia and leads to severe impairment of the patient, and even the final stage of the disease requires constant care of a mentally retarded older person. This book presents contemporary insights into the pathogenesis of Alzheimer's disease and currently used therapies that lead to slow the pro‐ gression of the disease and delay its occurrence.

This publication sums up the knowledge of the genetic, biochemical, and immunological fac‐ tors influenced in this dementive disease. It summarizes the pathophysiology observed both in Alzheimer's disease patients and in experimental studies. The book also contains the latest views on the molecular mechanism of dysfunction in this disease and life-long diagnosis.

We hope that this book may help in understanding the complex mechanisms of Alzheimer's disease pathogenesis and may be an inspiration to find factors to prevent this disease and to treat it effectively.

This book was created, thanks to the authors who wanted to share their scientific achieve‐ ments in the field of basic and clinical research in dementive diseases.

The editors would like to acknowledge the authors from various parts of the world and all other people who helped with the production of this book for their participation in this publication.

#### **Professor Jolanta Dorszewska, MDs, PhD**

Laboratory of Neurobiology Department of Neurology Poznan University of Medical Sciences Poland

#### **Professor Wojciech Kozubski, MD, PhD**

Department of Neurology Poznan University of Medical Sciences Poland

**Chapter 1**

**Provisional chapter**

**Amyloid Beta Hypothesis: Attention to β- and γ-**

**Amyloid Beta Hypothesis: Attention to β- and** 

DOI: 10.5772/intechopen.75629

The amyloid cascade hypothesis poses one possible explanation for the onset and progression of Alzheimer's disease (AD). With this respect, neurotoxic effect is attributed to soluble and diffusive amyloid-β (Aβ) oligomers. Aβ peptides are produced by proteolytic cleavage of the hydrophobic transmembrane portion of the amyloid precursor protein (APP) by successive action of β- and γ-secretases. Aβ peptides are generated in several isoforms, out of which the most pronounced are Aβ40 and Aβ42 being the major constituents of amyloid plaques found in AD patients' brains. Since the indisputable evidence pointed out to Aβ oligomers as toxic agents, several pathways to modulate or control the aggregation have been inspected. Given all these aspects, inhibitors of the β- and γ-secretases have gained the most attention. This chapter presents amyloid cascade hypothesis with current progress in

the development of β- and γ-secretase modulators to counteract the Aβ burden.

**Keywords:** Alzheimer's disease, amyloid beta, neurodegeneration, amyloid precursor

Despite the great progress in understanding pathogenetic and pathological processes associated with Alzheimer's disease (AD) in the last decade, the exact cause of AD still remains unrevealed. With the aim to clarify this cause, a number of hypotheses have been proposed, which involve, for example, the genetic hypothesis of AD based on malfunctioning variants of apolipoprotein E genes (*APOE*), the hyperphosphorylation of cytoskeletal proteins (especially of tau protein) or the theory of oxidative stress [1]. Importantly, AD is often explained by inflammatory processes in the brain, and metabolic processes leading to the formation and accumulation of the

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Jan Korabecny, Katarina Spilovska, Ondrej Soukup,

Jan Korabecny, Katarina Spilovska, Ondrej Soukup,

Additional information is available at the end of the chapter

protein, β-secretase, γ-secretase, presenilin

Additional information is available at the end of the chapter

**Secretase Modulators**

**γ-Secretase Modulators**

Rafael Dolezal and Kamil Kuca

Rafael Dolezal and Kamil Kuca

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

**Abstract**

**1. Introduction**

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

DOI: 10.5772/intechopen.75629

Jan Korabecny, Katarina Spilovska, Ondrej Soukup, Rafael Dolezal and Kamil Kuca Jan Korabecny, Katarina Spilovska, Ondrej Soukup, Rafael Dolezal and Kamil Kuca

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

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

#### **Abstract**

The amyloid cascade hypothesis poses one possible explanation for the onset and progression of Alzheimer's disease (AD). With this respect, neurotoxic effect is attributed to soluble and diffusive amyloid-β (Aβ) oligomers. Aβ peptides are produced by proteolytic cleavage of the hydrophobic transmembrane portion of the amyloid precursor protein (APP) by successive action of β- and γ-secretases. Aβ peptides are generated in several isoforms, out of which the most pronounced are Aβ40 and Aβ42 being the major constituents of amyloid plaques found in AD patients' brains. Since the indisputable evidence pointed out to Aβ oligomers as toxic agents, several pathways to modulate or control the aggregation have been inspected. Given all these aspects, inhibitors of the β- and γ-secretases have gained the most attention. This chapter presents amyloid cascade hypothesis with current progress in the development of β- and γ-secretase modulators to counteract the Aβ burden.

**Keywords:** Alzheimer's disease, amyloid beta, neurodegeneration, amyloid precursor protein, β-secretase, γ-secretase, presenilin

#### **1. Introduction**

Despite the great progress in understanding pathogenetic and pathological processes associated with Alzheimer's disease (AD) in the last decade, the exact cause of AD still remains unrevealed. With the aim to clarify this cause, a number of hypotheses have been proposed, which involve, for example, the genetic hypothesis of AD based on malfunctioning variants of apolipoprotein E genes (*APOE*), the hyperphosphorylation of cytoskeletal proteins (especially of tau protein) or the theory of oxidative stress [1]. Importantly, AD is often explained by inflammatory processes in the brain, and metabolic processes leading to the formation and accumulation of the

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

beta-amyloid (Aβ) [2]. Among all these theories, the amyloid metabolic cascade or the amyloid hypothesis and posttranslational modification of tau protein are considered as the main pathophysiological theories elucidating the outbreak of AD, although none of them is able to sufficiently explain the diversity of the biochemical and pathological abnormalities associated with the developed AD [3].

is cleaved by α-secretase to form a soluble extracellular fragment of sAPP-*α* and C83 fragment, which is split by *γ*-secretase, similar to the case of C99 [6]. However, the α-path does not release Aβ, but it leads to splitting out a short protein fragment p3. The exact physiological function of the fragment p3 has not been completely clarified yet [7]. In the course of the β-path, APP is first cleaved by the enzyme β-secretase (BACE-1) providing the *C*-terminal fragment of the length of 99 amino acids (C99) and a chain, which is transferred to the extracellular space. This remaining protein chain can be found in the literature under the acronym sAPP-β. Subsequently, C99 is cleaved by the activity of γ-secretase to short-length peptides consisting of 38–43 amino acids (referred to as Aβ) and the intracellular *C*-terminal domain (AICD). In most cases, formation of Aβ1–40 mainly occurs, although a longer and more toxic form Aβ1–42 sometimes can be also produced. However, recent findings also point to the fact that the production of Aβ can take place

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

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

3

Although APP is a part of the pathophysiological processes involved in AD, it is clear that the protein also carries out several natural physiological functions, particularly within the regulation of the synaptic transmission. It has been proved that transgenic mice with knock-out gene for APP exhibited an inability to transmit signals to the neuromuscular junction. Despite this fact, mice with upregulated expression of APP show better cognitive functions and spatial orientation. This is often rationalized by overproduction of AICD given by γ-secretase. The activity of APP is also put in a close connection with the metabolism of cholesterol. The neuroprotective character of APP was also demonstrated by suppression of the cyclin-dependent

The pathological role of APP is generally associated with the amyloidogenic way of its splitting. In general, many mutations of APP cause the autosomal dominant form of AD with early onset. Interestingly, genetic mutations in the adjacent part of the β-site of the APP gene induce neuroprotective effects, because Aβ is then produced only in a small extent. On the other hand, an excessive expression of the mutated APP forms associated with FAD (a redox cofactor in a number of biochemical reactions) leads to a loss of sense of smell, without dissemination of amyloid plaques, though. This observation is in a line with the loss of sense of

β-secretase (BACE-1; also referred to as Asp2 or memapsin 2) is an enzyme that breaks down APP in the site called β into the *C*-terminal fragment, from which monomers of Aβ are

even within the proteolytic cleavage of APP along the α-path (**Figure 1**) [8].

**3. Physiological function of amyloid precursor protein**

kinase 5 (CDK-5) activity in the process of tau hyperhosphorylation [9].

**4. Pathological features of amyloid precursor protein**

smell, which occurs in some patients in the early stages of AD [9].

**5. β-secretase**

According to the amyloid hypothesis, slow accumulation of extracellular senile plaques, composed of Aβ deposits, occurs in the beginning and further progresses into AD. On the other hand, a direct link between the toxic influence of Aβ, the impaired neuronal functions and the decline in memory functions still has not been fully clarified, but it is broadly accepted that Aβ undoubtedly plays a key role in the neuropathology of AD [4].
