(BQ) Part 2 book "Neuroanatomy and pathology of sporadic alzheimer’s disease" presentation of content: Alzheimer-Associated pathology in the extracellular space, alzheimer associated pathology in the extracellular space, final considerations, final considerations. | Chapter 8 Alzheimer-Associated Pathology in the Extracellular Space The Amyloid Precursor Protein and the Abnormal Protein Aβ A clear indicator for the end of the unusually protracted initial phase of the AD-associated pathological process is the abrupt appearance of an additional protein that appears in soluble form in the ISF: the small, ., 38–43, but mostly 40 or 42, amino acid-containing hydrophobic amyloid-β (Aβ) protein that at first is diffusely distributed in a monomeric state in a few circumscribed regions of the ISF but then rapidly forms insoluble aggregations, most of which are plaque-like entities. These Aβ-plaques develop with such consistency in the course of AD that they constitute one of its hallmark lesions (Masters and Selkoe 2012). The pathological Aβ peptide is generated by abnormal proteolytic processing of a physiological constituent of the nerve cell membrane, the amyloid precursor protein (APP) (Beyreuther and Masters 1991; Mattson 2004; Rajendran and Annaert 2012). APP is an integral membrane glycoprotein that presumably functions as a receptor. In addition, APP has been ascribed neurotropic and neuroprotective properties (Selkoe 1994; Selkoe et al. 2012). For the most part, APP is degraded without a trace by a process that does not permit Aβ production (Fig. ). During this process, α-secretase splices the APP and generates a soluble molecule (APPsα) that is released into the ISF. The remaining membrane-bound fragment (C83) is spliced by γ-secretase, and an additional non aggregation-prone fragment (P3) is released into the ISF, whereas the leftover APP C-terminal domain (AICD) remains in the neuronal cytoplasm (Fig. ) (Haass et al. 2012). Aβ comes into existence only under pathological conditions and originates via an abnormal degradation pathway. First, a long and soluble fragment (APPsβ) is cleaved from APP by a β-secretase (Fig. ). The membrane-anchored fragment (C99) is subject to further clearance via .
