Amyloid Beta, TNFα and FAIM-L; Approaching New Therapeutic Strategies for AD

ALZHEIMER’S DISEASE AND AMYLOID BETA Defining characteristics of Alzheimer’s disease (AD) are memory defects, synaptic alterations, presence of neuroinflammatory mediators, and a progressive neurodegeneration. One of the histopathological hallmarks of the disease is the presence of amyloid beta (Aβ) plaques; however, it seems that soluble oligomers, also called Aβ-derive-diffusible-ligands (ADDLs), are the really toxic species involved in the pathogenesis of AD (2). ADDLs are a blend of several sizes of oligomeric Aβ species (3). This suggests that most of the effects on the neurons cannot be attributed to interactions with specific receptors, but rather to interaction and alteration of the proteins and lipids within the cell membranes (4). ADDLs have been detected in AD patients (5), increasing their content with severity (6). Dimers isolated from AD brains impair LTP, enhance LTD, reduce dendritic spines density, and correlate with clinical state (7). Also, they are able to induce hyperphosphorylation of Tau and neuritic dystrophy (8). Soluble oligomers of Aβ are toxic for the neurons (9). They also cause synaptic dysfunction (10) through the activation of caspase-3 (11). Moreover, the inflammatory response characterized by the secretion of various products is initiated by the glial cells when these cells detect Aβ (12). Thus, Aβ appears to be a decisive trigger for the development of this neurodegenerative disorder.