Down syndrome (DS) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans. Interestingly, DS patients have an increased risk for cognitive decline and Alzheimer disease (AD). Several studies reveal that DS and AD neuropathology have many common features including deposition of senile plaques and neurofibrillary tangles, and cellular dysfunction such as increased oxidative stress and the impairment of protein homeostasis. A growing number of studies suggests that dysfunction of the unfolded protein response (UPR) plays a pivotal role in cellular dysfunction and death in AD. Recent data from our laboratory demonstrated the potential contribution of the UPR and more specifically the role of PERK-mediated disruption of protein synthesis in DS mouse models at different ages. Therefore, our project aim to investigate if restoring PERK pathway, by using a well-established PERK inhibitor (GSK2606414), could mitigate the early UPR activation and result in reduced brain pathology and improved cognition in a DS mouse model. We will use Ts2Cje mice that carry the trisomy of the Chr16 (homologous to human Chr21). The PERK inhibitor will be delivered by intranasal route to target directly the brain and the treatment of Ts2Cje will start at 1 month of age before the appearance of UPR stress, neuropathological hallmarks and cognitive decline. Pilot studies would be needed before the treatment to select the dose of the compound. For the treatment mice will be divided in two groups: Mice from group 1 will be treated for 2 months and sacrificed to test inhibition of PERK by immunochemical and immunofluorescence analysis. Mice from group 2 will be treated for 5 months, tested for cognitive performances and sacrificed to analyse AD-related pathology. Results obtained from this study aim to propose novel therapeutic strategies able to recover UPR alteration and reduce cognitive decline in DS individuals.
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 declines, including AD-like dementia in DS population, have a big impact on both cost of healthcare and the quality of life. Recently, the evidence of a strong contribute of protein dys-homeostasis has emerged in the development of neurodegenerative diseases. The novel idea underlying this project is that early chronic UPR activation represents a key molecular alteration leading to age- related cognitive decline in DS but also in normal population. Although notable strides have been made with regard to discerning the pathophysiological processes associated with dementia, pharmacological treatment trials to date have generally produced minimal or disappointing results. Increased ER stress can be considered a strong risk factor for the cognitive deterioration and, in particular, UPR over-activation may represent a novel target to slow or delay the DS- and age- related cognitive decline. Furthermore, deepening the knowledge of such pathogenic mechanisms (i.e., PERK, ATF6 and IRE1 pathways alterations) could allow to identify novel druggable targets.
Behavioral and functional analyses will provide invaluable information about the effectiveness of ER targeting drugs for DS and age-related brain disease. Moreover, it may also provide novel and suitable biomarkers associated with increased susceptibility to neurodegenerative and protein deposition disorders. Considering the exponential increase age-related disorders and life expectancy, this study will contribute to developing new therapeutic strategies against the global emergency of ageing of population. From a public health perspective, targeting and treating UPR alterations prior to the presence of clinical symptoms of the disease may lead to a drastic reduction in the socioeconomic costs associated with cognitive aging in DS and healthy population.
The impact of the proposed work is therefore substantial, especially in the light of the increased life expectancy of DS individuals, their high risk to develop AD-related cognitive decline and the increasing number of healthy population expected to be affected by dementia worldwide that. Therefore, if no effective treatments are found, this social and economic issue will reach unmanageable proportions by the near future.
It is also important to emphasize that the drugs selected to conduct this research is not been used in clinical setting and represents a novelty in the potential treatment of DS cognitive alterations. In addition, the evidence of its effectiveness could confirm the UPR as a prominent therapeutic target offering the opportunity for the development of further compounds targeting the UPR or innovative approaches in the field of neurodegenerative disorders.
At final, since increased chronic increased ER stress is a common feature of several neuropathology (e.g. Parkinson disease) the use of this therapeutic strategy could be repurposed in a different clinica setting. The use of intranasal route for drug administration represent a further innovation of this project. Indeed, targeting the brain with drugs in a selective manner is not simple. When given by a nasal spray, a compound is rapidly transported along the olfactory nerves into the central nervous system. As the blood-brain barrier is bypassed by this technique, the effects of a compound can be addressed in the brain. Within minutes of administration, an increase in concentrations in cerebrospinal fluid (CSF) can be measured whereas only small amounts reach the systemic circulation . 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.
In conclusion early preliminary findings strongly encourage to perform the present project, since the results generated by the investigators, each focusing on targets different but all equally crucial and strictly converging, may offer significant advances in the understanding pathophysiological mechanisms involved in DS- and age- associated cognitive decline. Interestingly the results may suggest novel and promising therapy that hopefully could have the potential not just to alleviate the symptoms but also to modify the course of the decline.