Identification and validation of COmmon pathways at the CrOssrOads of neurodegeneration and Neuroprotection (COCOON)
Progetto Alzheimer's disease (AD) is emerging as the most prevalent and socially disruptive illness of aging populations. Although AD is placing a considerable and increasing burden on society, it represents the largest unmet medical need in neurology, because currently incurable.
Genetic and pathological evidence strongly supports the amyloid cascade hypothesis, which states that Amyloid beta (Abeta) has an early and crucial role in AD. Abeta is liberated from the amyloid precursor protein (APP) by BACE and gamma-secretase activity. Alternatively, APP is cleaved within the Abeta domain by a disintegrin and metalloproteinase 10 (ADAM10), which prevents Abeta formation. Substantial data indicate Abeta oligomers as the primary influence driving synaptic dysfunction and spine loss. Importantly, spine structural alterations have been reported to be reversible pharmacologically, opening new therapeutic directions in AD.
In addition to Abeta, mounting evidences point to an important role of vascular pathology in AD. Indeed, “pure” AD is substantially less common than mixed dementias, in which tangles and plaques are accompanied by vascular changes. Of interest, the vascular contribution to AD might worse disease progression and can offer a potential window of opportunities for intervention strategies.
Therefore, AD pathogenesis is multifaceted and results from the integration of several crossing pathways that affects different cell types.
In this frame, COCOON will focus on proteins and pathways that have already been shown to be involved in AD neurodegeneration and in vascular pathology. ADAM10 and the C-Jun N-terminal Kinase-3 (JNK3) act directly on APP processing. ADAM10 prevents Abeta generation in neurons, but it is also found in the in atherosclerotic lesions, and JNK3 is responsible for APP phosphorylation favoring the amyloidogenic cleavage but is also a mediator of endothelial cell death. In astrocytes Thrombospondin 1 (TSP-1) secretion, retention and degradation can be dysregulated in presence of Abeta, while in the vessels contributes to reactive oxygen species generation. The major organelle involved in protein folding and quality control, the endoplasmic reticulum (ER), is dramatically affected in AD neurons and the abnormal levels of misfolded proteins at the ER engage the unfolded protein response (UPR) that in turn activates a quick response to restore proteostasis. Remarkably, UPR can be implicated in synaptic failure and in pathogenesis of endothelial dysfunction.
In this framework, COCOON will challenge the hypotheses that these neurodegenerative mechanisms/key proteins may inform more about neuroprotection pathways. Neuroprotection is defined as an intervention that favourably influences the disease process or underlying pathogenesis to produce lasting benefits for patients.
COCOON is designed to run for a period of 3 years, during which we expect to go beyond the state-of-the-art knowledge, which is blocked to the amyloid hypothesis. To this aim, the project will integrate interdisciplinary collaborations and is structured in 3 work packages (WP).
The WP1 will consist in a detailed characterization of these pathways in in vitro models and the expected results will shed light onto their contribute to the neuron-astrocyte crosstalk and in the neurogenesis. Moreover, miRNAs profiling will be performed in an early-stage mouse model of AD to identify miRNA involved in neurodegeneration.
The WP2 will take advantage human samples obtained from patients at early to late AD stages to assess pathways alterations and their potential correlation with vascular/amyloid burden in the patients.
The WP3 goal is to test potential interventional strategies targeting these pathways and aimed at promoting the neuroprotection. COCOON will test a FDA library to rescue TSP-1 and will assess potential therapeutic approaches based on UPR modulation. Moreover, the potential therapeutic eff