Down Syndrome (DS) individuals by the age of 40s are at increased risk to develop Alzheimer disease (AD). Several studies demonstrated that memory alterations could be linked to abnormalities in circulating insulin levels and/or defects in insulin signaling pathways. In this scenario, oxidative stress, mitochondrial dysfunction and accelerated aging are likely to act synergistically in promoting AD neuropathology in DS.
The prevalence of diabetes mellitus (T2DM) is higher in DS individuals than in the general population. As T2DM has been identified as a risk factor for AD, the concept developed that drugs that can treat successfully T2DM, such as glucagon like peptide 1 (GLP-1) analogs and inhibitors of its degradation (DPP-4 inhibitors), may also have neuroprotective properties is a promising strategy.
The present project will investigate the link between impaired insulin-pathway and cognition, on a well-established Tg mouse model of DS (Ts65Dn), further proposing DPP-4 as a novel therapeutic target for the prevention of AD in DS population. The neuroprotective effects of sitagliptin, a DPP-4 inhibitor, will be evaluated in DS mice by performing behavioral tests and analysis of insulin-signaling cascade and related pathways. In addition, by proteomics approaches, we will identify brain proteins whose expression levels or post-translational modifications could be significantly modulated by drug treatment. This is the first proposal focused to unravel the potential mechanisms through which impairment of insulin signaling affects cognitive decline in DS. No data on the beneficial role of sitagliptin and other DPP-4 inhibitors administration on learning and memory in DS exist as well as for the role of insulin resistance. The exact mechanisms involved are not fully elucidated and the applicability of drugs already approved for the treatment of diabetes to a broader range of insulin-related pathologies, including AD, needs to be demonstrated.
AD is the most common cause of dementia in the world and despite years of intense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in energy metabolism, increased oxidative stress, inflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Recently, evidence of a tight correlation between neurodegenerative and metabolic diseases has emerged. The novel idea underlying this project is that brain insulin resistance represents a key molecular alteration leading to age-related cognitive decline and may represent a novel target to slow or delay the age- and diet- related cognitive decline.
Intriguingly, the majority of DS individuals will develop AD by the age of 50ys, therefore DS may be considered a ¿human prodromal AD model¿ to study the molecular mechanisms involved in the progression to AD. Thus, in the last decade, growing studies have been focused to unravel both common and divergent pathways linking DS to AD neurodegeneration. This project aim to advance current knowledge by 1) Investigating the link between trisomy 21 and aberrant insulin signaling; 2) investigating the role of insulin signaling dysfunction in the development of AD-like dementia in DS; 3) setting up a novel intranasal protocol for drug administration, which allows CNS efficacy; 4) testing the neuroprotective effects of sitagliptin, an approved FDA drug for treatment of T2DM, in DS. So far, the drugs currently used to prevent or delay the onset of dementia have led to limited results, thus the development of new therapeutic approaches is a research priority. The potential beneficial effects of drugs currently used for treatment of T2DM are emerging but the neuroprotective mechanisms need to be completely addressed.
The results that will emerge from this project are expected to offer new options for the treatment of Alzheimer-like dementia by expanding the indications for agents that are already on the market. Indeed, the present project aims to advance biomedical research by repurposing the use of DPP-4 inhibitors in the treatment of neurological disorders, which are not currently numbered among the clinical uses of these drugs. This innovative approach has the extrinsic merit to be a promising therapeutic approach for AD-like dementia in DS patients but also for the general population at risk to develop AD. During the last decade the scientific community has devoted great attention to age-related cognitive decline and the number of these studies will most likely increase in the near future. Cognitive decline and dementia, including AD, have a big impact on both cost of healthcare and the quality of life.
Considering the exponential increase of obesity, metabolic syndrome as well as extension of lifespan, this project will contribute to developing new therapeutic strategies to prevent/slow the growing burden of age- and diet-related brain diseases. From a public health perspective, targeting and treating brain insulin resistance prior to the presence of clinical symptoms may lead to a significant reduction in the socioeconomic costs associated with cognitive aging. It is also important to highlight hat the drug selected to conduct this research is already approved for clinical use in the treatment of T2DM. So, the evidence of the effectiveness could offer an opportunity for an immediate assessment as a drug for the treatment of age-related cognitive decline and possibly promote the clinical "re-purpusing".
Further, the use of intranasal route is a step-forward in the effort to set up effective tissue-specific delivery of drugs. The intranasal pathway has been proposed as a non-invasive alternative route to deliver therapeutics to the brain. This route will bypass the blood-brain barrier and limit systemic side effects. Upon presentation at the nasal cavity, pharmacological agents reach the brain via the olfactory and trigeminal nerves. Previous studies by Craft and co-workers showed that insulin given by intranasal route (Frey WH II, US Patent 6313093, 2001) was able to reach the brain and exert its neuroprotective effects avoiding systemic effects.
The preliminary data we collected are promising and strongly support the experimental plan described.