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 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

Development of a Multicomponent Intervention to Prevent Alzheimer's Disease

Recent advances in vascular risk management have successfully reduced the prevalence of Alzheimer's Disease (AD) in several epidemiologic investigations. It is now widely accepted that cerebrovascular disease is both directly and indirectly involved in AD pathogenesis. Herein, we review the non-pharmacological and pharmacological therapeutic approaches for AD treatment. MIND [Mediterranean and DASH (Dietary Approaches to Stop Hypertension) Intervention for Neurodegenerative Delay] diet is an important dietary treatment for prevention of AD. Multi domain intervention including diet, exercise, cognitive training, and intensive risk managements also prevented cognitive decline in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) study. To confirm these favorable effects of life-style intervention, replica studies are being planned worldwide. Promotion of β-amyloid (Aβ) clearance has emerged as a promising pharmacological approach because insufficient removal of Aβ is more important than excessive Aβ production in the pathogenesis of the majority of AD patients. Most AD brains exhibit accompanying cerebral amyloid angiopathy, and Aβ distribution in cerebral amyloid angiopathy closely corresponds with the intramural periarterial drainage (IPAD) route, emphasizing the importance of Aβ clearance. In view of these facts, promotion of the major vascular-mediated Aβ elimination systems, including capillary transcytosis, the glymphatic system, and IPAD, have emerged as new treatment strategies in AD. In particular, the beneficial effects of cilostazol were shown in several clinical observation studies, and cilostazol facilitated IPAD in a rodent AD model. The COMCID (Cilostazol for prevention of Conversion from MCI to Dementia) trial, evaluating the efficacy of cilostazol for patients with mild cognitive impairment is currently ongoing in Japan. Such therapeutic approaches involving maintenance of cerebrovascular integrity and promotion of vascular-mediated Aβ clearance have the potential to be mainstream treatments for sporadic AD

Spin effects in single-electron transport through carbon nanotube quantum dots

We investigate the total spin in an individual single-wall carbon nanotube quantum dot with various numbers of electrons in a shell by using the ratio of the saturation currents of the first steps of Coulomb staircases for positive and negative biases. The current ratio reflects the total-spin transition that is increased or decreased when the dot is connected to strongly asymmetric tunnel barriers. Our results indicate that total spin states with and without magnetic fields can be traced by this method.Comment: 5pages, 5figures, accepted for publication in Phys. Rev.

A rarefied gas flow around a rotating sphere: diverging profiles of gradients of macroscopic quantities

The steady behaviour of a rarefied gas around a rotating sphere is studied numerically on the basis of the linearised ellipsoidal statistical model of the Boltzmann equation, also known as the ES model, and the Maxwell diffuse–specular boundary condition. It is demonstrated numerically that the normal derivative of the circumferential component of the flow velocity and that of the heat flux diverge on the boundary with a rate s⁻¹/² , where s is the normal distance from the boundary. Further, it is demonstrated that the diverging term is proportional to the magnitude of the jump discontinuity of the velocity distribution function on the boundary, which originates from the mismatch of the incoming and outgoing data on the boundary. The moment of force exerted on the sphere is also obtained for a wide range of the Knudsen number and for various values of the accommodation coefficient