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New Therapeutic Approaches for Alzheimer’s Disease and Cerebral Amyloid Angiopathy
Accumulating evidence has shown a strong relationship between Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA), and cerebrovascular disease. Cognitive impairment in AD patients can result from cortical microinfarcts associated with CAA, as well as the synaptic and neuronal disturbances ca...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2014
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202741/ https://www.ncbi.nlm.nih.gov/pubmed/25368578 http://dx.doi.org/10.3389/fnagi.2014.00290 |
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author | Saito, Satoshi Ihara, Masafumi |
author_facet | Saito, Satoshi Ihara, Masafumi |
author_sort | Saito, Satoshi |
collection | PubMed |
description | Accumulating evidence has shown a strong relationship between Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA), and cerebrovascular disease. Cognitive impairment in AD patients can result from cortical microinfarcts associated with CAA, as well as the synaptic and neuronal disturbances caused by cerebral accumulations of β-amyloid (Aβ) and tau proteins. The pathophysiology of AD may lead to a toxic chain of events consisting of Aβ overproduction, impaired Aβ clearance, and brain ischemia. Insufficient removal of Aβ leads to development of CAA and plays a crucial role in sporadic AD cases, implicating promotion of Aβ clearance as an important therapeutic strategy. Aβ is mainly eliminated by three mechanisms: (1) enzymatic/glial degradation, (2) transcytotic delivery, and (3) perivascular drainage (3-“d” mechanisms). Enzymatic degradation may be facilitated by activation of Aβ-degrading enzymes such as neprilysin, angiotensin-converting enzyme, and insulin-degrading enzyme. Transcytotic delivery can be promoted by inhibition of the receptor for advanced glycation end products (RAGE), which mediates transcytotic influx of circulating Aβ into brain. Successful use of the RAGE inhibitor TTP488 in Phase II testing has led to a Phase III clinical trial for AD patients. The perivascular drainage system seems to be driven by motive force generated by cerebral arterial pulsations, suggesting that vasoactive drugs can facilitate Aβ clearance. One of the drugs promoting this system is cilostazol, a selective inhibitor of type 3 phosphodiesterase. The clearance of fluorescent soluble Aβ tracers was significantly enhanced in cilostazol-treated CAA model mice. Given that the balance between Aβ synthesis and clearance determines brain Aβ accumulation, and that Aβ is cleared by several pathways stated above, multi-drugs combination therapy could provide a mainstream cure for sporadic AD. |
format | Online Article Text |
id | pubmed-4202741 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-42027412014-11-03 New Therapeutic Approaches for Alzheimer’s Disease and Cerebral Amyloid Angiopathy Saito, Satoshi Ihara, Masafumi Front Aging Neurosci Neuroscience Accumulating evidence has shown a strong relationship between Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA), and cerebrovascular disease. Cognitive impairment in AD patients can result from cortical microinfarcts associated with CAA, as well as the synaptic and neuronal disturbances caused by cerebral accumulations of β-amyloid (Aβ) and tau proteins. The pathophysiology of AD may lead to a toxic chain of events consisting of Aβ overproduction, impaired Aβ clearance, and brain ischemia. Insufficient removal of Aβ leads to development of CAA and plays a crucial role in sporadic AD cases, implicating promotion of Aβ clearance as an important therapeutic strategy. Aβ is mainly eliminated by three mechanisms: (1) enzymatic/glial degradation, (2) transcytotic delivery, and (3) perivascular drainage (3-“d” mechanisms). Enzymatic degradation may be facilitated by activation of Aβ-degrading enzymes such as neprilysin, angiotensin-converting enzyme, and insulin-degrading enzyme. Transcytotic delivery can be promoted by inhibition of the receptor for advanced glycation end products (RAGE), which mediates transcytotic influx of circulating Aβ into brain. Successful use of the RAGE inhibitor TTP488 in Phase II testing has led to a Phase III clinical trial for AD patients. The perivascular drainage system seems to be driven by motive force generated by cerebral arterial pulsations, suggesting that vasoactive drugs can facilitate Aβ clearance. One of the drugs promoting this system is cilostazol, a selective inhibitor of type 3 phosphodiesterase. The clearance of fluorescent soluble Aβ tracers was significantly enhanced in cilostazol-treated CAA model mice. Given that the balance between Aβ synthesis and clearance determines brain Aβ accumulation, and that Aβ is cleared by several pathways stated above, multi-drugs combination therapy could provide a mainstream cure for sporadic AD. Frontiers Media S.A. 2014-10-20 /pmc/articles/PMC4202741/ /pubmed/25368578 http://dx.doi.org/10.3389/fnagi.2014.00290 Text en Copyright © 2014 Saito and Ihara. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Saito, Satoshi Ihara, Masafumi New Therapeutic Approaches for Alzheimer’s Disease and Cerebral Amyloid Angiopathy |
title | New Therapeutic Approaches for Alzheimer’s Disease and Cerebral Amyloid Angiopathy |
title_full | New Therapeutic Approaches for Alzheimer’s Disease and Cerebral Amyloid Angiopathy |
title_fullStr | New Therapeutic Approaches for Alzheimer’s Disease and Cerebral Amyloid Angiopathy |
title_full_unstemmed | New Therapeutic Approaches for Alzheimer’s Disease and Cerebral Amyloid Angiopathy |
title_short | New Therapeutic Approaches for Alzheimer’s Disease and Cerebral Amyloid Angiopathy |
title_sort | new therapeutic approaches for alzheimer’s disease and cerebral amyloid angiopathy |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202741/ https://www.ncbi.nlm.nih.gov/pubmed/25368578 http://dx.doi.org/10.3389/fnagi.2014.00290 |
work_keys_str_mv | AT saitosatoshi newtherapeuticapproachesforalzheimersdiseaseandcerebralamyloidangiopathy AT iharamasafumi newtherapeuticapproachesforalzheimersdiseaseandcerebralamyloidangiopathy |