Open Access New Perspectives for the Treatment of Alzheimer’s Disease

Abstract: The hallmark pathologic lesions of Alzheimer’s disease (AD) are extracellular senile plaques, composed by Amiloid (A) peptide and intraneuronal neurofibrillary tangles, made of tau protein. According to the amyloid hypothe-sis, the increased production or decreased clearance of A peptide initiates a pathological process leading to neurodegen-eration, dementia and death. Under normal circumstances, the Amyloid Precursor Protein (APP) is cleaved by secretase, but, in pathological conditions, it is cleaved first by secretase (BACE) and subsequently by -secretase, to form A42 toxic peptide. Accumulation of A42 starts a cascade of events associated with neuronal and synaptic dys-function, inflammatory responses, hyperphosphorylation of tau protein and neuronal death. This theory identifies biologi-cal targets for disease-modifying treatments, including the modulation of APP metabolism, the reduction of A aggrega-tion or the enhancement of A clearance, and the reduction of inflammation. Regarding secretases, different approaches are under evaluation, primarily aiming to decrease - and -secretase. A promising approach is the modulation of A, with either vaccination or antiaggregation agents. Regarding inflammation, despite trials with Rofecoxib, Naproxen or Di-clofenac failed to slow progression of cognitive decline in patients with AD, Indomethacin showed positive results in de-laying cognitive decline. However, gastrointestinal toxicity was treatment-limiting, therefore other compounds have been developed, including Nitroflurbiprofen. In addition, Rosiglitazone, an oral anti-diabetic agent with anti-inflammatory properties, is currently in phase III study. A further approach aims to inhibit tau deposition with methyl thioninium chloride. In this review, the pathogenic steps leading to neurodegeneration will be discussed, together with an update of disease-modifying drugs under testing