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

Alzheimer's disease is a synaptic failure.

Literature Information

DOI	10.1126/science.1074069
PMID	12399581
Journal	Science (New York, N.Y.)
Impact Factor	45.8
JCR Quartile	Q1
Publication Year	2002
Times Cited	1989
Keywords	Alzheimer's disease, synaptic dysfunction, hippocampus, amyloid beta protein
Literature Type	Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Review
ISSN	0036-8075
Pages	789-91
Issue	298(5594)
Authors	Dennis J Selkoe

TL;DR

This study investigates the early clinical phase of Alzheimer's disease, which primarily manifests as a pure memory impairment linked to subtle changes in hippocampal synaptic efficacy before noticeable neuronal degeneration occurs. The findings suggest that these synaptic dysfunctions are driven by diffusible oligomeric assemblies of amyloid beta protein, highlighting a critical early target for therapeutic intervention in Alzheimer's disease.

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Alzheimer's disease · synaptic dysfunction · hippocampus · amyloid beta protein

Abstract

In its earliest clinical phase, Alzheimer's disease characteristically produces a remarkably pure impairment of memory. Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid beta protein.

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Primary Questions Addressed

1. What are the specific synaptic alterations observed in the hippocampus during the early stages of Alzheimer's disease?
2. How do oligomeric assemblies of amyloid beta protein contribute to synaptic dysfunction beyond memory impairment?
3. In what ways can synaptic efficacy be measured in patients with early Alzheimer's disease?
4. Are there potential therapeutic interventions that target synaptic failure in Alzheimer's disease before neuronal degeneration occurs?
5. How does the understanding of synaptic failure in Alzheimer's disease influence current research on neurodegenerative diseases?

Key Findings

Key Insights on Alzheimer's Disease as a Synaptic Failure

1. Research Background and Purpose:
   Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by memory impairment in its early clinical stages. This research aims to explore the underlying mechanisms of memory dysfunction in AD, particularly focusing on the role of synaptic alterations in the hippocampus—an area crucial for memory formation. The study seeks to establish a connection between synaptic efficacy and the presence of amyloid beta (Aβ) aggregates, positing that these oligomeric assemblies may precede and contribute to neuronal degeneration.

2. Main Methods and Findings:
   The study employs a combination of neurobiological techniques to assess synaptic function in the hippocampus of AD-afflicted models. Key findings indicate that before significant neuronal loss occurs, there are detectable changes in synaptic efficacy, particularly in the hippocampus, which is essential for memory. The evidence points towards diffusible oligomeric forms of the amyloid beta protein as the primary agents responsible for this synaptic dysfunction. These oligomers impair synaptic transmission without causing immediate neuronal death, highlighting a critical early stage in the pathogenesis of AD.

3. Core Conclusion:
   The research concludes that Alzheimer's disease may fundamentally be viewed as a synaptic failure rather than solely a consequence of neuronal loss. The initial synaptic dysfunction, driven by oligomeric assemblies of amyloid beta, is a crucial early event that leads to the characteristic memory impairment observed in AD patients. This perspective shifts the focus from a solely neurodegenerative view to one that emphasizes the importance of synaptic health in understanding and potentially treating AD.

4. Research Significance and Impact:
   This study has significant implications for the understanding of Alzheimer's disease. By identifying synaptic dysfunction as an early event in AD, it opens new avenues for therapeutic interventions aimed at preserving synaptic integrity rather than solely preventing neuronal death. This approach could lead to the development of drugs targeting the oligomeric forms of amyloid beta to restore synaptic function and potentially reverse memory impairment. Furthermore, the findings underscore the need for early detection and intervention strategies in AD that focus on synaptic health, which may enhance the efficacy of treatments and improve patient outcomes. Overall, this research contributes to a paradigm shift in how Alzheimer's disease is conceptualized and managed, emphasizing the significance of synaptic dynamics in neurodegenerative processes.

Literatures Citing This Work

1. Synaptic plasticity in animal models of early Alzheimer's disease. - Michael J Rowan;Igor Klyubin;William K Cullen;Roger Anwyl - Philosophical transactions of the Royal Society of London. Series B, Biological sciences (2003)
2. The glutamatergic system and Alzheimer's disease: therapeutic implications. - D Allan Butterfield;Chava B Pocernich - CNS drugs (2003)
3. Effect of environmental conditions on aggregation and fibril formation of barstar. - K Gast;A J Modler;H Damaschun;R Kröber;G Lutsch;D Zirwer;R Golbik;G Damaschun - European biophysics journal : EBJ (2003)
4. Imaging Alzheimer's disease. - Scott A Small - Current neurology and neuroscience reports (2003)
5. Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. - Yuesong Gong;Lei Chang;Kirsten L Viola;Pascale N Lacor;Mary P Lambert;Caleb E Finch;Grant A Krafft;William L Klein - Proceedings of the National Academy of Sciences of the United States of America (2003)
6. Age-dependent cerebrovascular abnormalities and blood flow disturbances in APP23 mice modeling Alzheimer's disease. - Nicolau Beckmann;Alexandra Schuler;Thomas Mueggler;Eric P Meyer;Karl-Heinz Wiederhold;Matthias Staufenbiel;Thomas Krucker - The Journal of neuroscience : the official journal of the Society for Neuroscience (2003)
7. Beta-amyloid prevents excitotoxicity via recruitment of glial glutamate transporters. - Atsushi Baba;Kazuhiko Mitsumori;Maki K Yamada;Nobuyoshi Nishiyama;Norio Matsuki;Yuji Ikegaya - Naunyn-Schmiedeberg's archives of pharmacology (2003)
8. Aging, amyloid, and Alzheimer's disease: a perspective in honor of Carl Cotman. - Dennis J Selkoe - Neurochemical research (2003)
9. Coupled reductions in brain oxidative phosphorylation and synaptic function can be quantified and staged in the course of Alzheimer disease. - Stanley I Rapoport - Neurotoxicity research (2003)
10. Cognitive reserve-mediated modulation of positron emission tomographic activations during memory tasks in Alzheimer disease. - Nikolaos Scarmeas;Eric Zarahn;Karen E Anderson;Lawrence S Honig;Aileen Park;John Hilton;Joseph Flynn;Harold A Sackeim;Yaakov Stern - Archives of neurology (2004)

... (1979 more literatures)

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