MaltSci 麦伴科研

Appearance

Curated Papers > High-impact authoritative literature on "Alzheimer's Disease"

Alzheimer's disease. ​

Literature Information ​

PMID21576255
JournalCold Spring Harbor perspectives in biology
Impact Factor8.4
JCR QuartileQ1
Publication Year2011
Times Cited214
KeywordsAlzheimer's disease, neurodegeneration, protein misfolding, amyloid protein, tau protein
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review
ISSN1943-0264
Issue3(7)
AuthorsDennis J Selkoe

TL;DR ​

This paper reviews the significant advances in understanding the molecular mechanisms of neurodegenerative diseases, particularly Alzheimer's disease, over the past thirty years, highlighting the role of misfolded proteins like amyloid β and tau in disease pathology. By elucidating the genotype-phenotype relationships of familial Alzheimer's, the research underscores potential therapeutic targets that could lead to new treatment strategies and clinical trials.

Search for more papers on MaltSci.com ​

Alzheimer's disease · neurodegeneration · protein misfolding · amyloid protein · tau protein

Abstract ​

Over the last three decades, advances in biochemical pathology and human genetics have illuminated one of the most enigmatic subjects in biomedicine--neurodegeneration. Eponymic diseases of the nervous system such as Alzheimer's, Parkinson's, and Huntington's diseases that were long characterized by mechanistic ignorance have yielded striking progress in our understanding of their molecular underpinnings. A central theme in these and related disorders is the concept that certain normally soluble neuronal proteins can misfold and aggregate into oligomers and amyloid fibrils which can confer profound cytotoxicity. Perhaps the foremost example, both in terms of its societal impact and how far knowledge has moved toward the clinic, is that of Alzheimer's disease (AD). Here, we will review the classical protein lesions of the disorder that have provided a road map to etiology and pathogenesis. We will discuss how elucidating the genotype-to-phenotype relationships of familial forms of Alzheimer's disease has highlighted the importance of the misfolding and altered proteostasis of two otherwise soluble proteins, amyloid β-protein and tau, suggesting mechanism-based therapeutic targets that have led to clinical trials.

MaltSci.com AI Research Service ​

Intelligent ReadingAnswer any question about the paper and explain complex charts and formulas
Locate StatementsFind traces of a specific claim within the paper
Add to KBasePerform data extraction, report drafting, and advanced knowledge mining

Primary Questions Addressed ​

  1. What are the latest findings on the interaction between lifestyle factors and Alzheimer's disease progression?
  2. How do emerging biomarkers like amyloid β oligomers and synaptic markers compare to traditional biomarkers in terms of diagnostic accuracy?
  3. What role does tau PET imaging play in the early diagnosis and differentiation of Alzheimer's disease from other types of dementia?
  4. How might the concept of preclinical Alzheimer's disease change the approach to early intervention and treatment strategies?
  5. What are the implications of combining anti-Alzheimer's therapies with lifestyle interventions for long-term patient outcomes?

Key Findings ​

Research Background and Objectives ​

The field of neurodegeneration has significantly advanced over the past thirty years, particularly in understanding diseases like Alzheimer's, Parkinson's, and Huntington's. Historically, these conditions were poorly understood at the mechanistic level. This review aims to synthesize current knowledge regarding the molecular mechanisms underlying Alzheimer's disease (AD), particularly focusing on the misfolding of soluble neuronal proteins and their implications for therapeutic strategies.

Main Methods/Materials/Experimental Design ​

The review employs a comprehensive analysis of existing literature on neurodegeneration, particularly emphasizing:

  • The biochemical pathways involved in protein misfolding.
  • Genotype-to-phenotype correlations in familial forms of Alzheimer's disease.
  • Mechanistic insights that have emerged from studying amyloid β-protein and tau.

The following flowchart illustrates the technical approach taken in the review:

Mermaid diagram

Key Results and Findings ​

  1. Protein Misfolding: The review highlights that normally soluble neuronal proteins, such as amyloid β and tau, can misfold and aggregate, leading to cytotoxic effects.
  2. Genotype-Phenotype Correlation: Insights from familial Alzheimer's cases have underscored the role of genetic factors in the pathogenesis of the disease.
  3. Therapeutic Targets: The understanding of misfolding mechanisms has led to the identification of potential targets for intervention, which are currently being explored in clinical trials.

Main Conclusions/Significance/Innovation ​

The review underscores the significance of protein misfolding in neurodegenerative diseases, particularly Alzheimer's. It presents a shift from descriptive pathology to a more mechanistic understanding, paving the way for targeted therapeutic strategies. The identification of amyloid β and tau as central players in the disease process offers innovative avenues for treatment development.

Research Limitations and Future Directions ​

  • Limitations: The review primarily focuses on established knowledge and may not encompass emerging theories or novel findings in neurodegeneration.
  • Future Directions: Further research is needed to explore the complexities of protein interactions and the role of other molecular pathways in neurodegeneration. Additionally, there is a call for more extensive clinical trials to validate potential therapeutic targets identified through these molecular insights.
SectionSummary
Research BackgroundAdvances in neurodegeneration understanding; focus on Alzheimer's disease.
Main Methods/DesignLiterature review, analysis of protein misfolding, genotype-phenotype correlations, identification of therapeutic targets.
Key ResultsMisfolding of amyloid β and tau; genotype-phenotype relationships highlighted; identification of potential therapeutic targets for clinical trials.
Main ConclusionsShift towards mechanistic understanding; innovative therapeutic strategies based on protein misfolding insights.
Limitations & Future DirectionsFocus on established knowledge; need for further exploration of molecular pathways and validation of therapeutic targets in clinical settings.

References ​

  1. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. - L Mucke;E Masliah;G Q Yu;M Mallory;E M Rockenstein;G Tatsuno;K Hu;D Kholodenko;K Johnson-Wood;L McConlogue - The Journal of neuroscience : the official journal of the Society for Neuroscience (2000)
  2. Alterations in synaptic transmission and long-term potentiation in hippocampal slices from young and aged PDAPP mice. - J Larson;G Lynch;D Games;P Seubert - Brain research (1999)
  3. Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. - M Hong;V Zhukareva;V Vogelsberg-Ragaglia;Z Wszolek;L Reed;B I Miller;D H Geschwind;T D Bird;D McKeel;A Goate;J C Morris;K C Wilhelmsen;G D Schellenberg;J Q Trojanowski;V M Lee - Science (New York, N.Y.) (1998)
  4. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. - S Gilman;M Koller;R S Black;L Jenkins;S G Griffith;N C Fox;L Eisner;L Kirby;M Boada Rovira;F Forette;J-M Orgogozo; - Neurology (2005)
  5. Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. - C A Lemere;J K Blusztajn;H Yamaguchi;T Wisniewski;T C Saido;D J Selkoe - Neurobiology of disease (1996)
  6. Expression of a ubiquitous, cross-reactive homologue of the mouse beta-amyloid precursor protein (APP). - H H Slunt;G Thinakaran;C Von Koch;A C Lo;R E Tanzi;S S Sisodia - The Journal of biological chemistry (1994)
  7. Microglial cells and amyloid beta protein (A beta) deposition; association with A beta 40-containing plaques. - D M Mann;T Iwatsubo;H Fukumoto;Y Ihara;A Odaka;N Suzuki - Acta neuropathologica (1995)
  8. Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer disease. - W Xia;J Zhang;R Perez;E H Koo;D J Selkoe - Proceedings of the National Academy of Sciences of the United States of America (1997)
  9. Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. - M C Irizarry;F Soriano;M McNamara;K J Page;D Schenk;D Games;B T Hyman - The Journal of neuroscience : the official journal of the Society for Neuroscience (1997)
  10. Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: implications for the pathogenesis and treatment of Alzheimer disease. - K C Evans;E P Berger;C G Cho;K H Weisgraber;P T Lansbury - Proceedings of the National Academy of Sciences of the United States of America (1995)

Literatures Citing This Work ​

  1. Neurodegeneration the RNA way. - Abigail J Renoux;Peter K Todd - Progress in neurobiology (2012)
  2. Genetics of dementia. - Henry L Paulson;Indu Igo - Seminars in neurology (2011)
  3. A human stem cell model of early Alzheimer's disease pathology in Down syndrome. - Yichen Shi;Peter Kirwan;James Smith;Glenn MacLean;Stuart H Orkin;Frederick J Livesey - Science translational medicine (2012)
  4. Inverse susceptibility to oxidative death of lymphocytes obtained from Alzheimer's patients and skin cancer survivors: increased apoptosis in Alzheimer's and reduced necrosis in cancer. - Maria I Behrens;Monica Silva;Felipe Salech;Daniela P Ponce;Daniela Merino;Mariana Sinning;Chengjie Xiong;Catherine M Roe;Andrew F G Quest - The journals of gerontology. Series A, Biological sciences and medical sciences (2012)
  5. Could immunomodulation be used to prevent prion diseases? - Thomas Wisniewski;Fernando Goñi - Expert review of anti-infective therapy (2012)
  6. The delicate balance between secreted protein folding and endoplasmic reticulum-associated degradation in human physiology. - Christopher J Guerriero;Jeffrey L Brodsky - Physiological reviews (2012)
  7. Unfolded protein stress in the endoplasmic reticulum and mitochondria: a role in neurodegeneration. - Sebastián Bernales;Marisol Morales Soto;Emma McCullagh - Frontiers in aging neuroscience (2012)
  8. Gender, sex steroid hormones, and Alzheimer's disease. - Rebekah S Vest;Christian J Pike - Hormones and behavior (2013)
  9. Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-β peptide and τ levels: target engagement, tolerability and pharmacokinetics in humans. - Maria L Maccecchini;Mee Young Chang;Catherine Pan;Varghese John;Henrik Zetterberg;Nigel H Greig - Journal of neurology, neurosurgery, and psychiatry (2012)
  10. Alzheimer's disease in a dish: promises and challenges of human stem cell models. - Jessica E Young;Lawrence S B Goldstein - Human molecular genetics (2012)

... (204 more literatures)

© 2025 MaltSci - We reshape scientific research with AI technology