The absence of early diagnostic biomarkers for Alzheimer¿s disease (AD), the most common form of dementia, allows the disease to progress until irreversible declines in cognitive functions and memory are detected. It is therefore imperative to develop early, non-invasive, and easily accessible diagnostic tools.
Due to the limited availability of samples and the obvious limitations of interventions in human subjects, it is very difficult to establish the time course of the progression of the disease, thus various mouse models have been employed to unravel the pathophysiology of AD.
The present project, RELIEVE, will take advantage of the observations that vision is early impaired in patients with AD and in mouse models of AD.
RELIEVE will investigate retinal biomarkers by analyzing retina, and olfactory epithelium in a mouse model starting from young, pre-symptomatic mice. We will investigate the appearance of AD signs as neurodegeneration, intracellular and extracellular protein aggregates, and neuroinflammation, along the disease progression using the 3xTg-AD mouse model bearing the human mutations in the genes encoding presenilin 1 (PS1M146V), amyloid precursor protein (APPSwe), and tau (MAPTP301L) which recapitulates most of the AD characteristics.
Data obtained in the RELIEVE project will pave the road for the development of new advanced cellular and microscopy techniques for the early diagnosis of AD.
POSSIBLE APPLICATIONS AND SOCIAL IMPACT
One of the major challenges of present time is human health. The increase of the human average lifespan has led to an increase in the incidence of aging-related pathologies and in particular of genetic and sporadic neurodegenerative diseases such as AD. Indeed, not only AD is at present the most common form of dementia, but the incidence of AD will increase as the population¿s age increases. The total number of affected individuals is expected to increase to a staggering number of 100 million people (Cummings J. et al. 2017, Alzheimers Dement 3:367-384) and therefore unravelling the molecular mechanisms underlying the progression of AD could spare the society a huge economical and emotional burden. Pharmaceutical companies are closing their research pipelines dedicated to the development of drugs for AD as the knowledge of molecular and functional bases of AD are too poorly understood.
There is a need to improve the quality of early AD diagnosis by looking for more economic and less invasive analysis. More appropriate biomarkers can allow fast and effective AD monitoring. Indeed, nowadays AD diagnosis is possible only when cognitive signs are present and for this reason most trials of new developed drugs have failed resulting in huge economic, time, and energy loss.
RELIEVE's mission is to help scientific, medical and pharmacological research to improve and accelerate the knowledge and diagnosis of AD. To this end, we aim to clearly identify pre-symptomatic hallmarks in the retina and to use them to identify the events that trigger AD pathogenesis cascade. We will start from the mouse as a model but it will not be difficult to translate the methods and results to humans. If the hypotheses of our study will be verified, from the experimental results we could elaborate a strategy for mass screening of AD and not only anticipate the diagnosis of patients, but even develop a methodology with predictive ability on the onset and progression of the disease. In fact, through the analysis of the retinal tissue, it will be possible to identify possible accumulations of protein aggregates and functional parameters and how they are modified in the presence of AD. This work will surely move the field of the AD studies forward and will offer new tools for non-invasive and early diagnosis of AD. This will be very important for the medical community and pharmaceutical companies to develop therapies at early stages to delay or stop the progression of AD, alleviating the pain of AD patients and their caregivers.
WP Deliverables:
Deliverable1: Results from WP1 will highlight if neuronal apoptosis may underlie visual deficits observed in AD patients before the appearance of classical AD signs occurring in the brain.
Deliverable2: Results from WP2 will indicate which molecular and cellular determinants typical of AD can be detected in the retina of pre-symptomatic 3xTg-AD mice, making the retina the ideal tissue for early AD diagnosis.
Deliverable3: Functional electrophysiological data will shed light on the retinal impairment as biomarkers for early AD diagnosis allowing the identification of functional targets to direct the development of non-invasive electrode-based early diagnostic instrumentation. Uniquely, this study will allow characterizing the time-course of neurodegenerative functional effects on the retina circuit and to identify best biomarker's targets (e.g. specific classes of RGCs) and visual stimuli to direct the development of non-invasive early diagnostic instrumentation as electroretinograms.
Deliverable 4: Results from WP4 will elucidate the beneficial or detrimental role of retinal microglia in physiological conditions and during AD progression, underlining the response given in sensorial districts.