Curated Papers > Highly Cited Authoritative Literature on "Alzheimer's Disease"

Alzheimer's disease: genes, proteins, and therapy.

Literature Information

DOI	10.1152/physrev.2001.81.2.741
PMID	11274343
Journal	Physiological reviews
Impact Factor	28.7
JCR Quartile	Q1
Publication Year	2001
Times Cited	2046
Keywords	Alzheimer's disease, genes, proteins, therapy, beta-amyloid
Literature Type	Journal Article, Review
ISSN	0031-9333
Pages	741-66
Issue	81(2)
Authors	D J Selkoe

TL;DR

This study highlights the significant advancements in understanding Alzheimer's disease (AD) through molecular and cell biology, particularly the genotype-phenotype relationships linked to familial forms of the disease, where mutations in four identified genes enhance amyloid beta-protein production. The discovery of presenilin as a potential gamma-secretase and the identification of beta-secretase have opened new avenues for drug development and early diagnosis, promising improved therapeutic and preventative strategies against this critical public health issue.

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Alzheimer's disease · genes · proteins · therapy · beta-amyloid

Abstract

Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid beta-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the beta-amyloid precursor protein by the protease called gamma-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought gamma-secretase, coupled with the recent identification of beta-secretase, has provided discrete biochemical targets for drug screening and development. Alternate and novel strategies for inhibiting the early mechanism of the disease are also emerging. The progress reviewed here, coupled with better ability to diagnose the disease early, bode well for the successful development of therapeutic and preventative drugs for this major public health problem.

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Primary Questions Addressed

1. What are the implications of the identified genes for genetic counseling in families with a history of Alzheimer's disease?
2. How do the mechanisms of amyloid beta-protein deposition vary between familial and sporadic forms of Alzheimer's disease?
3. What role do environmental factors play in the expression of genes linked to Alzheimer's disease?
4. How can advances in understanding presenilin proteins contribute to the development of personalized therapies for Alzheimer's patients?
5. What are the potential challenges in translating laboratory findings related to gamma-secretase into effective clinical treatments for Alzheimer's disease?

Key Findings

1. Research Background and Objectives: Alzheimer's disease (AD) is a complex neurodegenerative disorder primarily affecting the limbic and association cortices of the brain, leading to cognitive decline and memory loss. The objective of this research is to elucidate the biological mechanisms underlying AD by leveraging advancements in molecular and cellular biology. A particular focus is on understanding the genotype-to-phenotype relationships in familial forms of the disease, which have been genetically linked to specific mutations that influence the production and deposition of amyloid beta-protein (Aβ) in the brain.

2. Main Methods and Findings: The study highlights the interplay between basic and applied cell biology in advancing our understanding of AD. It identifies four key genes associated with inherited forms of AD that significantly contribute to increased levels of amyloid beta-protein. Notably, mutations in presenilin proteins, which are linked to the most aggressive forms of familial AD, affect the cleavage of the beta-amyloid precursor protein by gamma-secretase. This discovery suggests that presenilin may be the long-sought gamma-secretase, thus presenting a critical target for therapeutic intervention. Furthermore, the identification of beta-secretase has emerged as an additional target for drug development. The research also points to the emergence of alternative strategies for inhibiting the early mechanisms of AD, emphasizing a shift toward novel therapeutic approaches.

3. Core Conclusions: The findings underscore a significant advancement in understanding the molecular underpinnings of AD, particularly regarding the roles of presenilin and beta-secretase in amyloid beta-protein processing. This knowledge is pivotal for the development of targeted therapies aimed at mitigating the early stages of the disease. The ability to diagnose Alzheimer's disease at earlier stages enhances the prospects for successful therapeutic and preventative interventions.

4. Research Significance and Impact: This research is crucial as it bridges the gap between basic biological research and practical therapeutic applications. By identifying specific genetic and protein targets, the study paves the way for the development of new drug candidates that could alter the disease's trajectory. Given the increasing prevalence of Alzheimer's disease as a public health issue, these insights hold significant potential for improving patient outcomes and quality of life through early intervention and novel treatment strategies. The findings may also inspire future research directions in the field of neurodegenerative diseases, enhancing our overall understanding and approach to such complex disorders.

Literatures Citing This Work

1. beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. - E Masliah;E Rockenstein;I Veinbergs;Y Sagara;M Mallory;M Hashimoto;L Mucke - Proceedings of the National Academy of Sciences of the United States of America (2001)
2. Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. - B Halliwell - Drugs & aging (2001)
3. Psychogenomics: opportunities for understanding addiction. - E J Nestler - The Journal of neuroscience : the official journal of the Society for Neuroscience (2001)
4. Spotlight on BACE: the secretases as targets for treatment in Alzheimer disease. - C Dingwall - The Journal of clinical investigation (2001)
5. Alzheimer's beta-secretase, beta-site amyloid precursor protein-cleaving enzyme, is responsible for cleavage secretion of a Golgi-resident sialyltransferase. - S Kitazume;Y Tachida;R Oka;K Shirotani;T C Saido;Y Hashimoto - Proceedings of the National Academy of Sciences of the United States of America (2001)
6. Alzheimer's amyloid-beta as a preventive antioxidant for brain lipoproteins. - A Kontush - Cellular and molecular neurobiology (2001)
7. The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain. - Stefan F Lichtenthaler;Dirk Beher;Heike S Grimm;Rong Wang;Mark S Shearman;Colin L Masters;Konrad Beyreuther - Proceedings of the National Academy of Sciences of the United States of America (2002)
8. Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer's disease. - C Glabe - Journal of molecular neuroscience : MN (2001)
9. The beta-secretase, BACE: a prime drug target for Alzheimer's disease. - R Vassar - Journal of molecular neuroscience : MN (2001)
10. Implication of APP secretases in notch signaling. - D Hartmann;J Tournoy;P Saftig;W Annaert;B De Strooper - Journal of molecular neuroscience : MN (2001)

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