Abstract
Apolipoprotein E (apoE) remains the most important genetic risk factor for the development of Alzheimer's disease (AD). Still elusive, the role of apoE is under intense investigation. We propose that proteolysis of apoE in the brain leads to two major fragments, N- and C-terminal apoE, each of which would drive a different neuropathological pathway. N-terminal fragments of apoE are implicated in neurotoxicity, and C-terminal fragments might play a role in amyloid deposition and plaque formation. The greater risk of AD associated with the E4 isoform might relate to its greater neurotoxicity. Drugs that either directly inhibit the toxic effects of apoE or prevent the production of apoE fragments may provide novel therapeutic approaches to the treatment of AD and other disorders in which apoE is implicated.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / metabolism
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Alzheimer Disease / physiopathology
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Apolipoproteins E / antagonists & inhibitors*
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Apolipoproteins E / metabolism
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Brain / drug effects*
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Brain / metabolism
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Brain / physiopathology
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Humans
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Neurofibrillary Tangles / drug effects
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Neurofibrillary Tangles / metabolism
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology*
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Neurotoxins / antagonists & inhibitors
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Neurotoxins / metabolism
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Peptide Fragments / antagonists & inhibitors*
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Peptide Fragments / metabolism
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Peptide Hydrolases / drug effects
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Peptide Hydrolases / metabolism
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Plaque, Amyloid / drug effects
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Plaque, Amyloid / metabolism
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Protein Structure, Tertiary / drug effects
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Protein Structure, Tertiary / physiology
Substances
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Apolipoproteins E
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Neuroprotective Agents
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Neurotoxins
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Peptide Fragments
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Peptide Hydrolases