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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

“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.
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Figure 1: “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.

Mentions: In order to explore novel therapies in AD, we must consider the “AD malignant cycle” (Figure 1). In this scheme, cessation of Aβ overproduction is not sufficient to treat patients with sporadic AD, and important components of the cycle, brain ischemia, and CAA should also be noted. Insufficient Aβ clearance seems to be more crucial than Aβ overproduction in sporadic AD patients (Mawuenyega et al., 2010). Even in familial AD cases, the onset of dementia is often delayed until the fifth or sixth decade, suggesting that the aging-associated failure in clearance also plays a part in the pathogenesis of inherited types of the disease (Weller et al., 2008). Therefore, recent work has focused on the failure of Aβ elimination as the most important therapeutic targets and adopted a “neurovascular” approach as a strategy to tackle AD (Vardy et al., 2005; Deane et al., 2008; Carare et al., 2013).


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

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

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

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

Figure 1: “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.
Mentions: In order to explore novel therapies in AD, we must consider the “AD malignant cycle” (Figure 1). In this scheme, cessation of Aβ overproduction is not sufficient to treat patients with sporadic AD, and important components of the cycle, brain ischemia, and CAA should also be noted. Insufficient Aβ clearance seems to be more crucial than Aβ overproduction in sporadic AD patients (Mawuenyega et al., 2010). Even in familial AD cases, the onset of dementia is often delayed until the fifth or sixth decade, suggesting that the aging-associated failure in clearance also plays a part in the pathogenesis of inherited types of the disease (Weller et al., 2008). Therefore, recent work has focused on the failure of Aβ elimination as the most important therapeutic targets and adopted a “neurovascular” approach as a strategy to tackle AD (Vardy et al., 2005; Deane et al., 2008; Carare et al., 2013).

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