Alzheimer’s disease: discussing the “Bench-to-bed” and the “Bed-to-bench” path linking preclinical and clinical research

Alzheimer’s disease (AD) is a devastating progressive neurodegenerative disease that leads to cognitive deficits and brain atrophy. It is characterized by the presence of extracellular plaques rich in β-amyloid (Aβ) aggregates, intraneuronal neurofibrillary tangles rich in hyperphosphorylated Tau (NFTs), loss of synapse, neuroinflammation and neuronal death. As for most neurological disorders, translational research represents a driving strategy for advancement in AD diagnosis and therapy. A multidisciplinary bi-directions path links in vitro cell models, animal models and experimental animal science, neuropathological, genetic and biomarkers studies in human subjects (1) . The disease has been described at the beginning of 1900. However, most advancement was obtained over the last decades thanks to genetic and molecular studies. In particular, genetic studies have provided the first inside to develop hypothesis-oriented models. Based on mutation on three genes observed in a few hundreds of families in the word, the familial form of the disease has been described, that occurs in the presence of mutations of amyloid precursor protein (APP), presenilin 1 (PSEN1), presenilin 2 (PSEN2) genes. This early onset (EOAD) or familial (FAD) form of the disease accounts for 4-5% of cases. More complex is the genetic background for the late-onset (LOAD) or sporadic (SAD) form of AD, which account for most of the forms of the disease, were a risk factor has been associated to the ε4 allele of the APOE gene (2) . A relevant goal of translational medicine for AD, is to develop and characterize animal models that recapitulates all aspects of human Alzheimer's disease (3). A “perfect” animal model of disease should be able to replicate symptoms and lesions but also causes of the disease. Thus, APP, PSEN1/2 human mutations have been used to generate transgenic animals and mutated cells. For the purpose of this chapter, we will focus on APP-related models. We will illustrate how genetic studies in human have provided information to create cell and in vitro models, how these models have contributed to disease understanding, diagnosis improvement and therapy development, and how this multidisciplinary effort is now re-defining the APP-working hypothesis for AD.