**1. Introduction**

362 Neuroscience – Dealing with Frontiers

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104-113.

The pathology of Alzheimer Disease (AD) has been intensely studied in the last 20 years (Duyckaerts et al., 2009) because it is a progressive neurodegenerative disorder that causes dementia in approximately 10% of individuals older than 65 years (Hampel et al., 2010). AD occurs gradually; starting with the so called mild cognitive impairment (MCI) recognized by mild memory disturbances and noticed difficulties in performing more demanding cognitive tasks. With disease progression the decline in memory and cognition become more expressed and are accompanied by changes in personality and behaviour. In later stages of the disease loss of speech and movement is followed by total disability and finally death. A person with AD lives on average eight years after the onset of symptoms (Zerovnik, 2010). Actual studies are focused in many strategies for markers of susceptibility, early diagnostic, understanding of molecular mechanism, effective treatment and preventing strategies. According to Duyckaerts and coworkers (2009) AD could be divided in three broad chapters: lesions related to abnormal accumulation of proteins, those that are due to neural losses and finally those that are due to the reactive processes. According to abnormal accumulations proteins, AD is characterized by the presence of two types of neuropathological hallmarks: neurofibrillary tangles (NFTs) and neuritic plaques (NP). NFTs are intraneuronal aggregates of abnormally modified Tau (phosphorylated at non physiological sites, truncation, etc). NP are extracellular and mainly composed of amyloid βpeptide (AB) deposits (Martin et al., 2011). The most of the cases of AD are reported as "sporadic" pathway, because we still do not know what could be the factors that lead to this disease. Many hypotheses has been proposed, including immune system participation (Solomon &Frenkel, 2010), pathogens (Miklossy, 2011), oxidative stress responses, and more. At the end, in patients we can always find NFTs and NP in several regions of the brain

<sup>\*</sup> Both authors contributed in the same manner

Tau and Amyloid-β Conformational Change to β-Sheet

are generated after secretase cleavage.

protease inhibior (KPI) and a signal peptide (De Strooper, 2010).

Structures as Effectors in the Development of Alzheimer's Disease 365

cytoplasmic domain laregion C-terminal (figure 1B). The overall structure includes the position of a heparin binding domain, metal binding domains, sites of phosphorylation and glycosylation. Two of the isoforms (APP 751 and APP 770) have a domain Kunitz-type

Fig. 1. Characteristics of APP and processing (A) Exon structure of human APP gene 23. Exons are indicated by rectangles. Alternatively spliced exons are 7, 8 and 15. Functional protein domains are indicated by different colors. Distances between exons are not representative. (B) Schematic representation of human APP protein including the relative position of the α-, β- and γ-secretase cleavage sites. KPI: Kunitz-type protease inhibitor domain, AICD: APP intracellular domain, YENPTY: motif that binds he phosphotyrosine binding (PTB) domain of X11. (C) Schematic diagram of APP processing pathways. APP proteolytic catabolism includes two different pathways: an amyloidogenic pathway and a non-amyloidogenic pathway (constitutive secretary pathway). The different APP fragments

In brain tissue, APP can be processed in two ways: non-amyloidogenic and amyloidogenic pathway. In the non-amyloidogenic pathway, APP is first cleaved by α-secretase within the AB sequence, which releases the sAPPα ectodomain. Further processing of the resulting carboxyl terminal by γ-secretase results in the release of the p3 fragment and AICD (figure 1C) (Greenwald &Riek, 2010). The most prevalent area of research in AD studies the proteolytic generation of AB from APP. The β-secretase and γ-secretase cleave APP in the so-called amyloidogenic pathway β-secretase release the ectodomain sAPPβ, and the

(Braak &Braak, 1991). About these lesions, Braak and Braak (1991) established a relationship between the appearance of NP and NFTs with cognitive decline in post-mortem studies (Braak &Braak, 1991).

At the moment, AD can be diagnosed conclusively only post-mortem. However, advances in neuroimaging by magnetic resonance imaging (MRI) and by positron electron tomography (PET) allow researchers to see accumulation of amyloid plaques and NFTs in the living brain. In such a way, the course of the disease at various time points can be followed and an early diagnosis obtained. One, in principle, could even monitor the development/progression of the disease (Zerovnik, 2010). Several evidences demonstrate that under the formation of these lesions, are implicated in an important manner, conformational changes for Tau and amyloid β-peptide. Understanding the process at the molecular level is important for toxic aggregates could be stopped from forming or, alternatively, their removal could be accelerated. Antibodies directed against a common structural epitope shared by the prefibrillar oligomers could serve such a role. Common structural characteristics of amyloid fibrils are: predominantly β-sheet secondary structure, detected by specific dyes, and binding and a characteristic pattern seen by X-ray diffraction. By electron microscopy amyloigenic fibrils also are visualized allowing morphological studies (Zerovnik, 2010). In this chapter we focus on the importance of changes in conformation of both proteins during abnormal aggregation associated to AD.
