Mitsuru Shinohara 교수

Investigations of apolipoprotein E (APOE) gene, the major genetic risk modifier for Alzheimer's disease (AD), have yielded significant insights into the pathogenic mechanism. Among the three common coding variants, APOE*ε4 increases, whereas APOE*ε2 decreases the risk of late-onset AD compared with APOE*ε3. Despite increased understanding of the detrimental effect of APOE*ε4, it remains unclear how APOE*ε2 confers protection against AD. Accumulating evidence suggests that APOE*ε2 protects agains

Among the LDL receptor (LDLR) family members, the roles of LDLR-related protein (LRP)1 in the pathogenesis of Alzheimer's disease (AD), especially late-onset AD, have been the most studied by genetic, neuropathological, and biomarker analyses (clinical studies) or cellular and animal model systems (preclinical studies) over the last 25 years. Although there are some conflicting reports, accumulating evidence from preclinical studies indicates that LRP1 not only regulates the metabolism of amyloi

Recent studies suggest that subcortical structures, including striatum, are vulnerable to amyloid-β accumulation and other neuropathological features in familial Alzheimer's disease due to autosomal dominant mutations. We explored differences between familial and sporadic Alzheimer's disease that might shed light on their respective pathogenic mechanisms. To this end, we analysed 12 brain regions, including neocortical, limbic and subcortical areas, from post-mortem brains of familial Alzheimer'

APOE2 is associated with less cognitive decline during aging. This can occur independently of age-related synaptic/neuroinflammatory changes and amyloid accumulation. Higher levels of apoE and associated cholesterol metabolism in APOE2 carriers might contribute to this protective effect. Ann Neurol 2016;79:758-774.

Although the ε2 allele of apolipoprotein E (<i>APOE2</i>) benefits longevity, its mechanism is not understood. The protective effects of the <i>APOE</i>2 on Alzheimer's disease (AD) risk, particularly through their effects on amyloid or tau accumulation, may confound <i>APOE2</i> effects on longevity. Herein, we showed that the association between <i>APOE2</i> and longer lifespan persisted irrespective of AD status, including its neuropathology, by analyzing clinical datasets as well as animal m

Diabetes accelerates cognitive decline, in part, through accelerating vascular impairment in non-<i>APOE</i> ε4 carriers, but such effects are negligible in <i>APOE4</i> carriers, who themselves are already vulnerable to vascular impairment.

Obesity may accelerate cognitive decline in middle to early elderly cognitive normal individuals without <i>APOE4</i> likely by provoking vascular impairments. On the other hand, obesity may ease cognitive impairment in both individuals with dementia and individuals at the predementia stage, especially those with <i>APOE4</i>, through protecting against Alzheimer's pathologies. These results support that <i>APOE</i> genotype modifies the obesity paradox in dementia.

Accumulation of amyloid-β peptides is a dominant feature in the pathogenesis of Alzheimer's disease; however, it is not clear how individual amyloid-β species accumulate and affect other neuropathological and clinical features in the disease. Thus, we compared the accumulation of N-terminally truncated amyloid-β and full-length amyloid-β, depending on disease stage as well as brain area, and determined how these amyloid-β species respectively correlate with clinicopathological features of Alzhei

Apolipoprotein E (apoE) is linked to the risk for Alzheimer's disease (AD) and thus has been suggested to be an important therapeutic target. In our drug screening effort, we identified Ondansetron (OS), an FDA-approved 5-HT3 antagonist, as an apoE-modulating drug. OS at low micromolar concentrations significantly increased apoE secretion from immortalized astrocytes and primary astrocytes derived from apoE3 and apoE4-targeted replacement mice without generating cellular toxicity. Other 5-HT3 an

Clinical studies have indicated that obesity and diabetes are associated with Alzheimer's disease (AD) and neurodegeneration. Although the mechanisms underlying these associations remain elusive, the bidirectional interactions between obesity/diabetes and Alzheimer's disease (AD) may be involved in them. Both obesity/diabetes and AD significantly reduce life expectancy. We generated App^NL-F/wt knock-in; ob/ob mice by crossing App^NL-F/wt knock-in mice and ob/ob mice to inves

Despite the routine use of sandwich enzyme-linked immunosorbent assays (ELISAs) for quantifying tau levels in CSF and plasma, tau accumulations in the brains of patients with Alzheimer disease (AD) have rarely been evaluated by this method. Thus, by introducing several tau ELISAs that target different epitopes, we evaluated accumulated tau levels in postmortem brains depending on disease stage, brain areas, and other AD-related changes. Notably, tau levels in insoluble fraction determined by eac