Alzheimer´s disease, vascular dementia and type 2 diabetes mellitusTherapeutic implications

Resumen

Alzheimer´s disease (AD) is the leading cause of dementia followed by vascular dementia (VaD). While aging remains the most relevant risk factor to suffer dementia, type 2 diabetes mellitus (T2D) has also been positioned as another important risk element. The main neuropathological features of AD are amyloid and tau pathology, followed by neurodegeneration, all of which are accompanied by neuroinflammation that could ultimately constitute a link between dementia and T2D. Currently, dementias have not successful treatment. Given this, new therapeutic approaches are emerging, including natural extracts with potent anti-inflammatory effects or drugs to treat metabolic alterations. In this sense, we propose the use of natural extract from Mangifera indica Linn (MGF) to treat central pathology in an AD model (APP/PS1 mouse) as well as in a classical T2D model, the db/db mouse. Taking into account the close relationship between T2D and AD and that both pathologies are associated with aging, we have also characterized a mixed model, the APP/PS1xdb/db mouse at long term, when both pathologies have chronified. Moreover, we propose the use of an antidiabetic polypill (PP) to treat central complications in our mixed model. Our results showed on the one hand that MGF treatment improved cognitive decline as well as tau pathology, both in APP/PS1 and db/db mice. Inflammation was also diminished in both animal models. Likewise, MGF protects against metabolic dysfunction and vascular alterations in diabetic mice. On the other hand, the mixed AD-T2D model characterization revealed that the coexistence of both pathologies in the long term results in a synergist effect on cognitive decline, central tau and vascular pathology. Increased inflammation is also observed in APP/PS1xdb/db mice and amyloid natural history is altered towards more toxic soluble amyloid species. Our initial results after PP administration show that antidiabetic treatment not only rescues metabolic alterations. Furthermore, tau and amyloid pathologies were ameliorated, leading to an improvement of cognitive abilities. Our results reveal the potential use of anti-inflammatory and antidiabetic approaches to treat, prevent or delay dementias. Moreover, this first approach does not preclude the use of these drugs in combination with other specific anti-amyloid treatments.