New Perspectives for the Treatment of Alzheimer s Disease

The hallmark pathologic lesions of Alzheimer’s disease (AD) are extracellular senile plaques, composed by Amiloid β (Aβ) peptide and intraneuronal neurofibrillary tangles, made of tau protein. According to the amyloid hypothesis, the increased production or decreased clearance of Aβ peptide initiates a pathological process leading to neurodegeneration, dementia and death. Under normal circumstances, the Amyloid Precursor Protein (APP) is cleaved by α-secretase, but, in pathological conditions, it is cleaved first by β-secretase (BACE) and subsequently by γ-secretase, to form Aβ42 toxic peptide. Accumulation of Aβ42 starts a cascade of events associated with neuronal and synaptic dysfunction, inflammatory responses, hyperphosphorylation of tau protein and neuronal death. This theory identifies biological targets for disease-modifying treatments, including the modulation of APP metabolism, the reduction of Aβ aggregation or the enhancement of Aβ clearance, and the reduction of inflammation. Regarding secretases, different approaches are under evaluation, primarily aiming to decrease β- and γ-secretase. A promising approach is the modulation of Aβ, with either vaccination or antiaggregation agents. Regarding inflammation, despite trials with Rofecoxib, Naproxen or Diclofenac failed to slow progression of cognitive decline in patients with AD, Indomethacin showed positive results in delaying 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 diseasemodifying drugs under testing.