New therapeutic approaches for Alzheimer's disease and cerebral amyloid angiopathy.
paper
Cited
Public
- Authors
- Saito, Satoshi; Ihara, Masafumi
- Year
- 2014
- Journal
- Frontiers in aging neuroscience
- PMID
- 25368578
- DOI
- 10.3389/fnagi.2014.00290
- PMCID
- PMC4202741
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.
“AD malignant cycle”. Aβ overproduction impairs Aβ elimination leading to vascular smooth muscle cells (vSMC) degeneration, cerebral ischemia, and microinfarcts. Ischemia also induces Aβ overproduction. Such vicious circle consists of core pathology in sporadic AD. Note that cessation of Aβ overproduction is not sufficient to sever the cycle.
Aβ clearance: 3-d mechanism. Aβ is mainly eliminated by the following mechanisms: (1) enzymatic/glial degradation, (2) transcytotic delivery, and (3) perivascular drainage.
Cilostazol with 3 Arrows: triple effects toward potential resolution of dementia. Cilostazol, a selective inhibitor of PDE3, has pleiotropic capabilities of suppressing Aβ production in neurons, enhancing Aβ clearance through perivascular drainage system, and inhibiting platelet aggregation (anti-platelet effects).
Cilostazol reduced Aβ deposition. Hippocampal images obtained from 17-month-old homozygous Tg-SwDI mice, a model of CAA, treated with vehicle (A,B) or cilostazol (C) for 15 months show that cilostazol treatment reduced levels of Aβ deposits in the hippocampus compared with vehicle treatment. Scale bars indicate 100 μm. (A) HE staining. (B,C) Thioflavin-S staining.
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| Name | Type |
|---|---|
| 125I-labeled albumin local | drug |
| 125I-labeled Aβ1-40 local | drug |
| ACE | gene |
| AD model mice local | cohort |
| AD patients | cohort |
| AD with CVD local | cohort |
| aged wild-type mice local | cohort |
| AGER local | gene |
| aging | phenotype |
| Aging-associated clearance failure local | phenotype |
| Aging mouse brain local | cohort |
| agonist | drug |
| Alpha-2-macroglobulin local | drug |
| Alzheimer's disease | phenotype |
| Alzheimer’s disease | phenotype |
| amnestic MCI local | phenotype |
| amnestic mild cognitive impairment | phenotype |
| Amyloid beta | drug |
| Amyloid-beta | drug |
| Amyloid beta oligomers local | drug |
| Anti‑platelet drug local | drug |
| apoE | gene |
| APOE ε4 | gene |
| APP | gene |
| APP Dutch/Iowa mutant local | variant |
| APP-transgenic mice | cohort |
| arterial pulsations local | phenotype |
| arterial stiffness local | phenotype |
| Arterial stiffness local | phenotype |
| Arterioles local | anatomy |
| arteriolosclerosis local | phenotype |
| Arteriolosclerosis local | phenotype |
| aspirin | drug |
| associative memory local | phenotype |
| Atrial natriuretic peptide local | drug |
| Aβ1-40 local | drug |
| Aβ accumulation | phenotype |
| Aβ clearance | phenotype |
| Aβ deposits local | phenotype |
| Aβ-induced tauopathy local | phenotype |
| Aβ levels | phenotype |
| Aβ pathology local | phenotype |
| Aβ plaque local | phenotype |
| Aβ production | phenotype |
| Aβ protein local | drug |
| Basement membranes of capillary walls local | anatomy |
| beta-amyloid | drug |
| bexarotene | drug |
| Bilateral common carotid artery local | anatomy |
| Binswanger disease local | phenotype |
| blood | drug |
| blood-brain barrier | anatomy |
| Blood vessels local | anatomy |
| brain | anatomy |
| brain ischemia local | phenotype |
| Brain ischemia local | phenotype |
| brain parenchyma local | anatomy |
| CAA local | phenotype |
| CAA model mice local | cohort |
| caffeine | drug |
| cAMP | drug |
| Capillaries local | anatomy |
| Capillary walls local | anatomy |
| Captopril local | drug |
| caudate nucleus | anatomy |
| central nervous system | anatomy |
| cerebral amyloid angiopathy local | phenotype |
| Cerebral amyloid angiopathy local | cohort |
| Cerebral amyloid angiopathy local | phenotype |
| cerebral Aβ levels local | phenotype |
| cerebral hemorrhage | phenotype |
| Cerebral microinfarcts local | phenotype |
| Cerebral microvessels local | anatomy |
| cerebrospinal fluid | drug |
| Cerebrovascular disease | phenotype |
| Cervical lymph nodes local | anatomy |
| cGMP | drug |
| Cholesterol efflux | phenotype |
| cilostazol local | drug |
| Cilostazol local | drug |
| Cilostazol Stroke Prevention Study 2 local | cohort |
| Circle of Willis local | anatomy |
| Cisterna magna local | anatomy |
| cognition | phenotype |
| cognitive decline | phenotype |
| Conventional lymphatic vessels local | anatomy |
| cortex | anatomy |
| Cortical microhemorrhage local | phenotype |
| Cortical microinfarcts local | phenotype |
| CREB1 | gene |
| Deep cervical lymph nodes local | anatomy |
| dementia | phenotype |
| diabetes | phenotype |
| dobutamine local | drug |
| donepezil local | drug |
| donepezil-treated patients with clinically probable AD local | cohort |
| Elderly patients local | cohort |
| Enkephalins local | drug |
| Extracranial vessels local | anatomy |
| Familial Alzheimer's disease local | cohort |
| fluorescent tracers local | drug |
| Fluorescent tracers local | drug |
| glucose intolerance | phenotype |
| glymphatic pathway local | anatomy |
| Hemodynamic fluctuation local | phenotype |
| Hemorrhage | phenotype |
| Hemorrhagic stroke | phenotype |
| hippocampus | anatomy |
| hyperinsulinemia | phenotype |
| hypertension | phenotype |
| hypoperfusion local | phenotype |
| Hypoperfusion/ischemia local | phenotype |
| hypoxia | phenotype |
| IDE | gene |
| IDE deficient mice local | cohort |
| Immunized AD patients local | cohort |
| impaired arterial pulsation local | phenotype |
| Impaired arterial pulsation local | phenotype |
| Indian ink local | drug |
| Infarctions local | phenotype |
| inferior colliculus | anatomy |
| Inflammatory burden local | phenotype |
| insulin | drug |
| insulin resistance | phenotype |
| Intracranial arteries local | anatomy |
| intranasal insulin local | drug |
| ISF | drug |
| juvenile familial Alzheimer's disease local | phenotype |
| laminin | drug |
| Leptomeningeal arteries local | anatomy |
| Leptomeningeal Arteries local | anatomy |
| lipid peroxidation | phenotype |
| Liver X receptor local | drug |
| Lobar hemorrhage local | phenotype |
| LRP1 | gene |
| lymphatic congestion local | phenotype |
| Lymphatic endothelial cell proliferation local | phenotype |
| Lymphatic endothelial cell stabilization local | phenotype |
| Lymphatic perivascular drainage system local | anatomy |
| Major cerebral arteries local | anatomy |
| Malignant tumors local | phenotype |
| Medical Research Council Cognitive Function and Aging Study local | cohort |
| Meningeal arteries local | anatomy |
| Middle cerebral artery local | anatomy |
| Middle Cerebral Artery local | anatomy |
| middle temporal gyrus | anatomy |
| MMP9 | gene |
| neprilysin local | gene |
| Neprilysin local | gene |
| neurogenesis | phenotype |
| neuronal loss | phenotype |
| nitric oxide | drug |
| non-demented elderly adults local | cohort |
| normal control patients local | cohort |
| Nun study local | cohort |
| occipital cortex | anatomy |
| Oligodendrocyte precursor cell differentiation local | phenotype |
| other dementing disorders local | phenotype |
| patients with MCI local | cohort |
| PDE3 local | gene |
| perivascular drainage system local | anatomy |
| perivascular drainage system local | phenotype |
| Perivascular lymphatic drainage system local | anatomy |
| PPARγ | gene |
| protein kinase A | drug |
| PSEN1 | gene |
| PSEN2 | gene |
| pulse wave velocity | phenotype |
| Pulse wave velocity local | drug |
| Radiolabeled tracers local | drug |
| rat model of chronic cerebral hypoperfusion local | cohort |
| Receptor-associated protein local | drug |
| rolipram | drug |
| senescence-accelerated mice local | cohort |
| Senescence-accelerated mice local | cohort |
| senile plaques | phenotype |
| Sildenafil local | drug |
| Small venules local | anatomy |
| Small vessel injury local | phenotype |
| solutes local | drug |
| somatostatin receptor agonist local | drug |
| spatial learning | phenotype |
| spatial memory | phenotype |
| Sporadic Alzheimer's disease local | cohort |
| striatum | anatomy |
| stroke | phenotype |
| Synaptic disturbance local | phenotype |
| synaptic function | phenotype |
| Systemic lymphatic vessels local | anatomy |
| tachykinins | drug |
| tauopathy | phenotype |
| tau phosphorylation | drug |
| tau protein | drug |
| TTP488 local | drug |
| Tunica adventitia local | anatomy |
| Tunica media local | anatomy |
| type 1 small vessel disease local | phenotype |
| Type 1 small vessel disease local | phenotype |
| type 2 small vessel disease local | phenotype |
| Type 2 small vessel disease local | phenotype |
| type 3 diabetes local | phenotype |
| Vascular changes local | phenotype |
| Vascular dementia local | phenotype |
| vascular integrity local | phenotype |
| vasoactive drugs local | drug |
| White matter change local | phenotype |
| young wild-type mice local | cohort |
| β-secretase | drug |
| γ-secretase | drug |
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In this knowledge base
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| A Case of Cerebral Amyloid Angiopathy With Recurrent Hemorrhagic and Ischemic Strokes Under Direct Oral Anticoagulant Therapy for Atrial Fibrillation. | Uemura J et al. | — | 2025 | → |
| Aβ<sub>40</sub> Improves Cerebrovascular Endothelial Function via NOX4-Dependent Hydrogen Peroxide Release. | Heller E et al. | — | 2025 | → |
| Efficacy and Safety of Cilostazol in Mild Cognitive Impairment: A Randomized Clinical Trial. | Saito S et al. | — | 2023 | → |
| Insights into the Pathophysiology of Alzheimer's Disease and Potential Therapeutic Targets: A Current Perspective. | Rajah Kumaran K et al. | — | 2023 | → |
| New Perspectives of Taxifolin in Neurodegenerative Diseases. | Yang R et al. | — | 2023 | → |
| Oxidative Stress in Health and Disease. | Reddy VP | — | 2023 | → |
| Conditioned medium from amniotic fluid mesenchymal stem cells could modulate Alzheimer's disease-like changes in human neuroblastoma cell line SY-SY5Y in a paracrine manner. | Hasanpour M et al. | — | 2022 | → |
| Azeliragon ameliorates Alzheimer's disease via the Janus tyrosine kinase and signal transducer and activator of transcription signaling pathway. | Yang L et al. | — | 2021 | → |
| Circulating AQP4 Levels in Patients with Cerebral Amyloid Angiopathy-Associated Intracerebral Hemorrhage. | Marazuela P et al. | — | 2021 | → |
| Molecularly imprinted polymer nanoparticles-based electrochemical chemosensors for selective determination of cilostazol and its pharmacologically active primary metabolite in human plasma. | Jyoti et al. | — | 2021 | → |
| Perivascular spaces and brain waste clearance systems: relevance for neurodegenerative and cerebrovascular pathology. | Gouveia-Freitas K et al. | — | 2021 | → |
| Taxifolin: A Potential Therapeutic Agent for Cerebral Amyloid Angiopathy. | Saito S et al. | — | 2021 | → |
| The Role of Cilostazol and Inflammation in Cognitive Impairment After Ischemic Stroke. | Huang LC et al. | — | 2021 | → |
| An automated method for segmentation and quantification of blood vessels in histology images. | Bukenya F et al. | — | 2020 | → |
| Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA): Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer's disease-Opportunities for Therapy. | Carare RO et al. | — | 2020 | → |
| Drug Development for Central Nervous System Diseases Using In vitro Blood-brain Barrier Models and Drug Repositioning. | Morofuji Y et al. | — | 2020 | → |
| Drug Repositioning for Alzheimer's Disease: Finding Hidden Clues in Old Drugs. | Ihara M et al. | — | 2020 | → |
| Low-Dose Phosphodiesterase III Inhibitor Reduces the Vascular Amyloid Burden in Amyloid-β Protein Precursor Transgenic Mice. | Yakushiji Y et al. | — | 2020 | → |
| Potential Role of Venular Amyloid in Alzheimer's Disease Pathogenesis. | Morrone CD et al. | — | 2020 | → |
| Potential Therapeutic Approaches for Cerebral Amyloid Angiopathy and Alzheimer's Disease. | Tanaka M et al. | — | 2020 | → |
| Quantitative proteomic profiling of white matter in cases of cerebral amyloid angiopathy reveals upregulation of extracellular matrix proteins and clusterin. | Manousopoulou A et al. | — | 2020 | → |
| Repositioning medication for cardiovascular and cerebrovascular disease to delay the onset and prevent progression of Alzheimer's disease. | Lee H et al. | — | 2020 | → |
| Roles of vascular risk factors in the pathogenesis of dementia. | Takeda S et al. | — | 2020 | → |
| Accumulation of Amyloid Beta (Aβ) Peptide on Blood Vessel Walls in the Damaged Brain after Transient Middle Cerebral Artery Occlusion. | Martins AH et al. | — | 2019 | → |
| Cerebral Amyloid Angiopathy and Neuritic Plaque Pathology Correlate with Cognitive Decline in Elderly Non-Demented Individuals. | Malek-Ahmadi M et al. | — | 2019 | → |
| Development of a Multicomponent Intervention to Prevent Alzheimer's Disease. | Saito S et al. | — | 2019 | → |
| Novel Therapeutic Potentials of Taxifolin for Amyloid-β-associated Neurodegenerative Diseases and Other Diseases: Recent Advances and Future Perspectives. | Tanaka M et al. | — | 2019 | → |
| PDE3 Inhibitors Repurposed as Treatments for Age-Related Cognitive Impairment. | Yanai S et al. | — | 2019 | → |
| Pharmacological Potential of Cilostazol for Alzheimer's Disease. | Ono K et al. | — | 2019 | → |
| Platelet-generated amyloid beta peptides in Alzheimer's disease and glaucoma. | Inyushin M et al. | — | 2019 | → |
| Pleiotropic neuroprotective effects of taxifolin in cerebral amyloid angiopathy. | Inoue T et al. | — | 2019 | → |
| Cilostazol May Decrease Plasma Inflammatory Biomarkers in Patients with Recent Small Subcortical Infarcts: A Pilot Study. | Saji N et al. | — | 2018 | → |
| Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells? | Prytkova I et al. | — | 2018 | → |
| Intraventricular infusion of clusterin ameliorated cognition and pathology in Tg6799 model of Alzheimer's disease. | Qi XM et al. | — | 2018 | → |
| Linking Atrial Fibrillation with Alzheimer's Disease: Epidemiological, Pathological, and Mechanistic Evidence. | Ihara M et al. | — | 2018 | → |
| Peak exercise stroke volume effects on cognitive impairment in community-dwelling people with preserved ejection fraction. | Sugie M et al. | — | 2018 | → |
| Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing. | Boland B et al. | — | 2018 | → |
| A<i>β</i> Peptide Originated from Platelets Promises New Strategy in Anti-Alzheimer's Drug Development. | Inyushin MY et al. | — | 2017 | → |
| APP/Aβ structural diversity and Alzheimer's disease pathogenesis. | Roher AE et al. | — | 2017 | → |
| Cerebral Microvascular Accumulation of Tau Oligomers in Alzheimer's Disease and Related Tauopathies. | Castillo-Carranza DL et al. | — | 2017 | → |
| Emerging concepts in sporadic cerebral amyloid angiopathy. | Charidimou A et al. | — | 2017 | → |
| Endothelial LRP1 - A Potential Target for the Treatment of Alzheimer's Disease : Theme: Drug Discovery, Development and Delivery in Alzheimer's Disease Guest Editor: Davide Brambilla. | Storck SE et al. | — | 2017 | → |
| In Vitro Modeling of Blood-Brain Barrier with Human iPSC-Derived Endothelial Cells, Pericytes, Neurons, and Astrocytes via Notch Signaling. | Yamamizu K et al. | — | 2017 | → |
| Long-term cilostazol administration ameliorates memory decline in senescence-accelerated mouse prone 8 (SAMP8) through a dual effect on cAMP and blood-brain barrier. | Yanai S et al. | — | 2017 | → |
| Proteomic differences in brain vessels of Alzheimer's disease mice: Normalization by PPARγ agonist pioglitazone. | Badhwar A et al. | — | 2017 | → |
| Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy. | Saito S et al. | — | 2017 | → |
| The role of amyloid beta clearance in cerebral amyloid angiopathy: more potential therapeutic targets. | Qi XM et al. | — | 2017 | → |
| 1,25-Dihydroxyvitamin D3 regulates expression of LRP1 and RAGE in vitro and in vivo, enhancing Aβ1-40 brain-to-blood efflux and peripheral uptake transport. | Guo YX et al. | — | 2016 | → |
| A multicenter, randomized, placebo-controlled trial for cilostazol in patients with mild cognitive impairment: The COMCID study protocol. | Saito S et al. | — | 2016 | → |
| Development of Cerebral Microbleeds in the APP23-Transgenic Mouse Model of Cerebral Amyloid Angiopathy-A 9.4 Tesla MRI Study. | Reuter B et al. | — | 2016 | → |
| Hypertension and Dementia: Epidemiological and Experimental Evidence Revealing a Detrimental Relationship. | Perrotta M et al. | — | 2016 | → |
| Influence of Low-Dose Aspirin on Cerebral Amyloid Angiopathy in Mice. | Hattori Y et al. | — | 2016 | → |
| Interaction between cerebrovascular disease and Alzheimer pathology. | Saito S et al. | — | 2016 | → |
| The pattern recognition reagents RAGE VC1 and peptide p5 share common binding sites and exhibit specific reactivity with AA amyloid in mice. | Kennel SJ et al. | — | 2016 | → |
| Beta-Amyloid and Tau-Protein: Structure, Interaction, and Prion-Like Properties. | Tatarnikova OG et al. | — | 2015 | → |
| Can insulin signaling pathways be targeted to transport Aβ out of the brain? | Vandal M et al. | — | 2015 | → |
| Current and future implications of basic and translational research on amyloid-β peptide production and removal pathways. | Bohm C et al. | — | 2015 | → |
| Impact of Insulin Degrading Enzyme and Neprilysin in Alzheimer's Disease Biology: Characterization of Putative Cognates for Therapeutic Applications. | Jha NK et al. | — | 2015 | → |
| Interaction between therapeutic interventions for Alzheimer's disease and physiological Aβ clearance mechanisms. | Morrone CD et al. | — | 2015 | → |
| Melatonin Attenuates Memory Impairment, Amyloid-β Accumulation, and Neurodegeneration in a Rat Model of Sporadic Alzheimer's Disease. | Rudnitskaya EA et al. | — | 2015 | → |
| Non-neuronal and neuronal BACE1 elevation in association with angiopathic and leptomeningeal β-amyloid deposition in the human brain. | Xue ZQ et al. | — | 2015 | → |
| The feasibility of quantitative MRI of perivascular spaces at 7T. | Cai K et al. | — | 2015 | → |