Aβ degradation

Malcolm Leissring, Takaomi C. Saido

Research output: Chapter in Book/Report/Conference proceedingChapter

6 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is characterized by abnormal accumulation of the amyloid β-protein (Aβ) in brain regions important for memory and cognition. Aβ is a normal product of cellular metabolism (Haass et al. 1992) derived from the amyloid precursor protein (APP) by the successive action of the β-and γ-secretases (see Chapters 4 and 3, respectively). The production of Aβ is normally counterbalanced by its elimination via any of several processes, including (i) proteolytic degradation, (ii) cell-mediated clearance (which may itself involve proteolytic degradation), (iii) active transport out of the brain (Chapter 10), and (iv) deposition into insoluble aggregates (Chapter 6). While the relative importance of these different pathways remains to be established, a growing body of evidence suggests that proteolytic degradation is a particularly important determinant of cerebral Aβ levels and, by extension, of Aβ-associated pathology. Characterization of the molecular and pathological phenotypes of familial AD-causing gene mutations identified largely in 1990's played a central role in establishing that Aβ is indeed most like to play a central role in AD pathogenesis and that the increased generation of Aβ, particularly Aβ42, is the cause of Aβ accumulation in the brains of familial AD patients harboring mutations in APP or presenilin-1 or-2 (Chapter 1). Nonetheless, there is no clear evidence that increased Aβ production precedes Aβ deposition in most cases of sporadic AD, which account for more than 90% of all AD cases. Moreover, pathological and biochemical analysis of sporadic AD indicates that a selective increase in Aβ42 production, as observed in familial AD, is not likely to be a cause of most sporadic AD cases (Lemere et al. 1996; Scheuner et al. 1996). These facts led to the proposal that decreased catabolism rather than increased anabolism of Aβ may be a primary cause for sporadic AD (Saido 1998), for which aging is by far the strongest risk factor, as down-regulation rather than up-regulation of metabolism is a general feature of aging (Lu et al. 2004). Nonetheless, widespread interest in the proteolytic degradation of Aβ did not take hold until the turn of the 21st Century. This contrasts starkly with studies of Aβ production, which enjoyed intense scrutiny over this same period. While several factors may have contributed to this state of affairs, it can be argued that Aβ degradation is a more challenging topic to address experimentally because it relies upon studies in the living animal to an extent that studies on Aβ production do not. Notably, whereas all of the components involved in Aβ production (APP, β-and γ-secretases) can be recapitulated faithfully and economically within cell culture, in contrast cell culture experiments are of limited value for investigating Aβ degradation, particularly in determining the relative importance of different candidate proteases in regulating the overall economy of brain Aβ. As described in greater detail below, a key turning point in the field came with the first study that was explicitly designed to examine Aβ degradation in the living animal (Iwata et al. 2000). In addition to identifying neprilysin (NEP) as one of the principal Aβ-degrading proteases, this study also served to highlight the significance of Aβ degradation to AD pathogenesis generally, thereby igniting interest in a previously underappreciated aspect of Aβ metabolism. It now appears quite likely that the aging-dependent reduction of Aβ degradation may be a primary cause of Aβ accumulation in aged brains and thus of sporadic AD development. The rise in interest in Aβ degradation spawned by this and other discoveries is impressive: whereas only a few papers addressing this topic were published in the entire 20 th Century, subsequent growth in this field in just a few years has been so great that it is now impossible to cite all the papers in this field in a chapter of this length. Accordingly, this chapter will focus principally on biomedical evidence pertaining to the in vivo relevance of Aβ-degrading proteases and their therapeutic potential, and will rely on Chapter 1 to summarize the large body of evidence examining possible genetic linkage between Aβ-degrading proteases and AD. Individual Aβ-degrading proteases will be considered in turn, followed by a general discussion of future research directions.

Original languageEnglish (US)
Title of host publicationAlzheimer's Disease: Advances in Genetics, Molecular and Cellular Biology
PublisherSpringer US
Pages157-178
Number of pages22
ISBN (Print)0387351345, 9780387351346
DOIs
StatePublished - 2007
Externally publishedYes

Fingerprint

Alzheimer Disease
Peptide Hydrolases
Brain
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor
Cell Culture Techniques
Presenilin-1
Serum Amyloid A Protein
Neprilysin
Mutation
Genetic Linkage
Active Biological Transport
Cognition
Up-Regulation
Down-Regulation
Pathology
Phenotype

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Leissring, M., & Saido, T. C. (2007). Aβ degradation. In Alzheimer's Disease: Advances in Genetics, Molecular and Cellular Biology (pp. 157-178). Springer US. https://doi.org/10.1007/978-0-387-35135-3_10

Aβ degradation. / Leissring, Malcolm; Saido, Takaomi C.

Alzheimer's Disease: Advances in Genetics, Molecular and Cellular Biology. Springer US, 2007. p. 157-178.

Research output: Chapter in Book/Report/Conference proceedingChapter

Leissring, M & Saido, TC 2007, Aβ degradation. in Alzheimer's Disease: Advances in Genetics, Molecular and Cellular Biology. Springer US, pp. 157-178. https://doi.org/10.1007/978-0-387-35135-3_10
Leissring M, Saido TC. Aβ degradation. In Alzheimer's Disease: Advances in Genetics, Molecular and Cellular Biology. Springer US. 2007. p. 157-178 https://doi.org/10.1007/978-0-387-35135-3_10
Leissring, Malcolm ; Saido, Takaomi C. / Aβ degradation. Alzheimer's Disease: Advances in Genetics, Molecular and Cellular Biology. Springer US, 2007. pp. 157-178
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