Editorial [Hot Topic: Alzheimer Drug Design Based on the Amyloid Hypothesis (Executive Editors: D. Munoz-Torrero and P. Camps)]

Alzheimer's disease (AD), one of the current major health problems, is already approaching epidemic proportions, affecting millions of people worldwide, while an effective curative or preventive therapy still remains elusive. Ever since the discovery of the direct relationship between most cholinergic markers in the central nervous system and the cognitive and functional decline experienced by AD patients, as well as the subsequent establishment of the cholinergic hypothesis of AD thirty years ago, cholinomimetic agents, and, in particular, acetylcholinesterase inhibitors (AChEIs) have assumed a prominent position in our reduced therapeutic arsenal for the treatment of this disease. However, these treatments have always been regarded as merely symptomatic. Consequently, there is an urgent need for alternative therapies targeting the underlying mechanisms of the disease, thus allowing the interruption or reversal of AD progression. After the sequenciation of the β-amyloid peptide (Aβ) and the recognition of this species as the primary component of the senile plaques present in the brains of AD patients twenty years ago, this peptide emerged as the ideal therapeutic target, directly related to the pathogenesis of the disease. Even if the primary cause of AD still remains speculative, during the last decade, mounting evidence point toward the misprocessing of the amyloid precursor protein (APP) and the increase in formation and aggregation of the resulting neurotoxic Aβ peptide as the major and early event in the pathogenesis of AD. The generally recognized central role of Aβ formation and aggregation in the etiology of AD has made the amyloid hypothesis, the rationale basis for the current most promising therapeutic approaches to AD, which are called to be the first therapeutic options for AD in virtue of their disease-modifying potential. Unfortunately, the clinical trials implying the most advanced of the amyloid-directed therapies, such as Aβ vaccination (AN1792), were recently cancelled by safety issues, after having shown very interesting beneficial effects on both plaque burden and cognitive decline. While safer alternative immunization approaches are being actively pursued, other amyloid-directed therapies are beginning to enter human trials. Several lines of evidence point out a connection between both the amyloid and the cholinergic hypotheses of AD, which seem not to be neither independent nor mutually exclusive. APP processing, and consequently, Aβ formation, as well as Aβ aggregation seem to be under cholinergic control, which has renewed the interest for cholinomimetic agents, especially for AChEIs, as disease-modifying amyloid- and cholinergic-directed drug candidates. In this issue, the current status of vaccination against AD is discussed, as well as other potentially disease-modifying therapies which specifically target Aβ production, aggregation or neurotoxicity. In Chapter 1, Dr. McLaurin and colleagues [1] discuss the benefits and drawbacks of the firstly developed Aβ immunization therapies and present several novel approaches to immunotherapy, re-designed from the initial vaccines, which hold promise for safer and effective human use. The enzymes responsible for Aβ synthesis from APP, β- and γ-secretases, have emerged as very attractive pharmacological targets. In Chapters 2 and 3, promising anti-Alzheimer drug candidates with the pharmacological profile of β- and γ-secretase inhibitors are presented. Thus, Dr. Kiso and colleagues [2] provide an insightful overview of the different strategies aimed at decreasing Aβ production through disruption of the pathological APP processing, with a particular emphasis on the rational design of peptidomimetic and non-peptidomimetic β-secretase inhibitors, while Dr. Ziani-Cherif and colleagues [3] have provided a comprehensive review focused on the design of the different structural classes of γ-secretase inhibitors, including a discussion on the potential problematic of these compounds due to the promiscuity of this protease to cleave a broad amount of physiologically important proteins such as Notch. Dr. Weggen and colleagues [4] present an exciting review of non-steroidal anti-inflammatory drugs and related compounds which, through direct modulation of γ- secretase, display preferential lowering activity for the most neurotoxic form of Aβ (Aβ42), without eliciting toxic effects derived from the processing of the Notch receptor and other γ-secretase substrates. In Chapter 5, Dr. Yamada and colleagues [5] present several classes of compounds which interfere with the amyloid cascade after the synthesis of Aβ, by inhibition of the formation of Aβ fibrils and destabilization of the preformed fibrils as key molecules for the development of preventives and therapeutics for AD.....