## 3 Alzheimer's Disease
### Neuropathology  
The major pathological hallmarks of AD are the set-up of extracellular amyloid plaques and intraneuronal neurofibrillary tangles (NFTs) in the brain. Although plaques and tangles are also identified in cognitively normal age-matched controls, their density and distribution are significantly more severe in AD patients [17]. Amyloid plaques are mainly composed of the amyloid-\(\beta\) (A\(\beta\)) peptide that accumulate in the extracellular cortex [18]. The 40 amino acids-peptide is the most common form of A\(\beta\) in humans and is called A\(\beta\)40, whereas a 42-amino-acid-long fragment, called A\(\beta\)42, is less abundant. The only difference is that A\(\beta\)42 has two additional amino acid residues at the C-terminus [19]. However, A\(\beta\)42 has been associated with AD because it is more prone to aggregation than A\(\beta\)40, and thus would be deposited before A\(\beta\)40 [20], leading to the formation of these amyloid plaques. The gene of the amyloid precursor protein (APP) that originates the A\(\beta\) peptide is located in chromosome 21 in humans with three major isoforms arising from alternative splicing [21]. However, the physiological function of APP, despite intensive research, is not yet fully disclosed. Three distinct secretases (\(\alpha\), \(\beta\), or \(\gamma\)) can induce cleavage of full-length APP, which thus undergoes different sequential proteolytic processing. In the nonamyloidogenic pathway, APP is first cleaved by \(\alpha\)-secretase (non-neurotoxic, \"normal\" cleavage), releasing a large soluble ectodomain of APP (sAPP-\(\alpha\)) into the extracellular space. Opposed to A\(\beta\), sAPP-\(\alpha\) plays an important role in survival and in neuronal plasticity, showing a protective effect against excitotoxicity. sAPP-\(\alpha\) also regulates the proliferation of neural stem cells, being instrumental for early neural development [22]. On the contrary, in the amyloidogenic processing, APP is first cleaved by \(\beta\)-secretase (potentially neurotoxic, \"abnormal\" cleavage), releasing another soluble ectodomain of APP (sAPP-\(\beta\)) into the extracellular space. Upon \(\alpha\) or \(\beta\)-cleavage, the respective carboxyl terminal fragments (CTFs) of APP (\(\alpha\)-CTF and \(\beta\)-CTF) are kept in the cell membrane and suffer \(\gamma\)-secretase-mediated cleavage. Subsequent to this, \(\gamma\)-cleavage, \(\alpha\)-CTF and \(\beta\)-CTF generate p83 and A\(\beta\), respectively, (Figure 1). It should be noted that \(\gamma\)-secretase cleavage occurs in the transmembrane domain, even though the exact site may vary. Indeed, major sites of \(\gamma\)-secretase cleavage are the A\(\beta\)40 and 42 positions [14], resulting in the production of A\(\beta\)40 or A\(\beta\)42, i.e., two main forms of A\(\beta\) consisting, respectively, of either 40 or 42 amino acid residues. The prevalent theory of AD pathogenesis is currently accepted to be the amyloid hypothesis, suggesting the accumulation of insoluble forms of A\(\beta\) as the primary pathological process, which results from the imbalance between A\(\beta\) production and A\(\beta\) clearance [23]. Indeed, the A\(\beta\)40/A\(\beta\)42 ratio is key in the set-up of this disease. A\(\beta\)42 is the predominant form of A\(\beta\) found in the brain parenchyma of AD patients, whereas A\(\beta\)40 is mostly found in the cerebral vasculature [24]. Since A\(\beta\)42 is the most soluble form, it has the risk of oligomerizing to form A\(\beta\)-fibrils and protofibrils responsible for the formation of amyloid plaques. Although amyloid plaques are assumed to be nontoxic, the formation of amyloid oligomers may be responsible for neurotoxicity. As a result, the amyloid cascade would lead to the clinical syndrome of AD [14]. This cascade of events includes local oxidation, inflammation, excitotoxicity (due to excessive glutamate) and tau hyperphosphorylation [14].