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New therapeutic approaches for Alzheimer's disease and cerebral amyloid angiopathy.

Saito S, Ihara M - Front Aging Neurosci (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center , Suita , Japan.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

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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Figure 4: 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.

Mentions: Among varieties of vasoactive drugs, cilostazol, a selective inhibitor of type 3 phosphodiesterase (PDE), is likely to be a promising agent for AD and CAA (Figure 3). PDE3 can hydrolyze both cAMP and cGMP, while increasing cAMP level is a major pharmacological effect of cilostazol (Ikeda, 1999). PDE3 is widely expressed in central nervous system and up-regulated in Aβ-positive vessels, especially in vascular smooth muscle cells (vSMC) (Maki et al., 2014), suggesting the possibility that PDE3 inhibition could be therapeutic for CAA. Cilostazol possesses multiple effects, such as increasing pulse rate (Shinohara et al., 2010) and arterial elasticity (Han et al., 2013), prolonging pulse duration time (Aruna and Naidu, 2007), and dilating cerebral vessels (Tanaka et al., 1989; Birk et al., 2004a,b); such vasoactive actions may promote efficiency of perivascular drainage. In support of this, clearance of fluorescent soluble Aβ tracers is significantly enhanced in cilostazol-treated CAA model mice, thereby resulting in maintenance of vascular integrity, amelioration of Aβ deposits (Figure 4), and prevention of cognitive decline (Maki et al., 2014). Memory-preserving activity of cilostazol has been demonstrated in aged wild-type mice (Yanai et al., 2014) and a rat model of chronic cerebral hypoperfusion (Watanabe et al., 2006), suggesting that cilostazol could be a potential disease modifying therapy of AD and other dementing disorders.


New therapeutic approaches for Alzheimer's disease and cerebral amyloid angiopathy.

Saito S, Ihara M - Front Aging Neurosci (2014)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4202741&req=5

Figure 4: 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.
Mentions: Among varieties of vasoactive drugs, cilostazol, a selective inhibitor of type 3 phosphodiesterase (PDE), is likely to be a promising agent for AD and CAA (Figure 3). PDE3 can hydrolyze both cAMP and cGMP, while increasing cAMP level is a major pharmacological effect of cilostazol (Ikeda, 1999). PDE3 is widely expressed in central nervous system and up-regulated in Aβ-positive vessels, especially in vascular smooth muscle cells (vSMC) (Maki et al., 2014), suggesting the possibility that PDE3 inhibition could be therapeutic for CAA. Cilostazol possesses multiple effects, such as increasing pulse rate (Shinohara et al., 2010) and arterial elasticity (Han et al., 2013), prolonging pulse duration time (Aruna and Naidu, 2007), and dilating cerebral vessels (Tanaka et al., 1989; Birk et al., 2004a,b); such vasoactive actions may promote efficiency of perivascular drainage. In support of this, clearance of fluorescent soluble Aβ tracers is significantly enhanced in cilostazol-treated CAA model mice, thereby resulting in maintenance of vascular integrity, amelioration of Aβ deposits (Figure 4), and prevention of cognitive decline (Maki et al., 2014). Memory-preserving activity of cilostazol has been demonstrated in aged wild-type mice (Yanai et al., 2014) and a rat model of chronic cerebral hypoperfusion (Watanabe et al., 2006), suggesting that cilostazol could be a potential disease modifying therapy of AD and other dementing disorders.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center , Suita , Japan.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus