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Recent epidemiological studies suggest that diabetes mellitus is a strong risk factor for Alzheimer disease. However, the underlying mechanisms remain largely unknown. In this study, to investigate the pathophysiological interaction between these diseases, we generated animal models that reflect the pathologic conditions of both diseases. We crossed Alzheimer transgenic mice (APP23) with two types of diabetic mice (ob/ob and NSY mice), and analyzed their metabolic and brain pathology. The onset of diabetes exacerbated Alzheimer-like cognitive dysfunction without an increase in brain amyloid-β burden in double-mutant (APP + -ob/ ob) mice. Notably, APP + -ob/ob mice showed cerebrovascular inflammation and severe amyloid angiopathy. Conversely, the cross-bred mice showed an accelerated diabetic phenotype compared with ob/ob mice, suggesting that Alzheimer amyloid pathology could aggravate diabetes. Similarly, APP + -NSY fusion mice showed more severe glucose intolerance compared with diabetic NSY mice. Furthermore, high-fat diet feeding induced severe memory deficits in APP + -NSY mice without an increase in brain amyloid-β load. Here, we created Alzheimer mouse models with early onset of cognitive dysfunction. Cerebrovascular changes and alteration in brain insulin signaling might play a pivotal role in this relationship. These findings could provide insights into this intensely debated association.β-amyloid | insulin T he incidences of Alzheimer disease (AD) and diabetes mellitus (DM) are increasing at an alarming rate and have become major public health concerns (1, 2). Interestingly, numerous epidemiological studies demonstrated that diabetic patients have a significantly higher risk of developing AD, independent of the risk for vascular dementia (2, 3). These findings raise the possibility that DM may affect fundamental AD pathogenesis. A neuropathological hallmark of AD is β-amyloid peptide (Aβ) accumulation in the brain (4). Of importance, recent data showed a clear relationship between insulin and Aβ metabolism (5-7). For example, insulin increased the extracellular Aβ level by modulating γ-secretase activity (6), or by increasing its secretion from neurons (5). Insulin-degrading enzyme, a major Aβ-degrading enzyme, might be competitively inhibited by insulin, resulting in decreased Aβ degradation (7). In addition, the brain insulin-degrading enzyme level was decreased in a hyperinsulinemic Alzheimer animal model (8). Nevertheless, unexpectedly, there is no evidence that the typical pathological hallmarks of AD, including amyloid plaque, are increased in the brain of diabetic patients (9, 10). Thus, DM could affect the pathogenesis of AD through other mechanisms than modulating Aβ metabolism. One possible mechanism is cerebrovascular alteration, a common pathological change in DM and AD. Accumulating evidence suggests the importance of Aβ-induced cerebrovascular dysfunction in AD (11). Moreover, cerebrovascular disease is a major complication of DM. Vascular inflammation or oxidative stress mediated by the ...

Tau pathology is known to spread in a hierarchical pattern in Alzheimer’s disease (AD) brain during disease progression, likely by trans-synaptic tau transfer between neurons. However, the tau species involved in inter-neuron propagation remains unclear. To identify tau species responsible for propagation, we examined uptake and propagation properties of different tau species derived from postmortem cortical extracts and brain interstitial fluid of tau-transgenic mice, as well as human AD cortices. Here we show that PBS-soluble phosphorylated high-molecular-weight (HMW) tau, though very low in abundance, is taken up, axonally transported, and passed on to synaptically connected neurons. Our findings suggest that a rare species of soluble phosphorylated HMW tau is the endogenous form of tau involved in propagation and could be a target for therapeutic intervention and biomarker development.