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y-secretase inhibitors for treating Alzheimer\\\'s disease: rationale and clinical data

Francesco Panza, Vincenza Frisardi, Bruno P Imbimbo, Davide Seripa, Vincenzo Solfrizzi, Alberto Pilotto

There are no drugs available for slowing down the rate of deterioration of patients with Alzheimer’s disease (AD). With the aim of altering the natural history of the disease, the pharmaceutical industry has designed and developed several compounds inhibiting g-secretase, the enzymatic complex generating b-amyloid (Ab) peptides (Ab1–40 and Ab1–42), believed to be involved in the pathophysiological cascade of AD, from amyloid precursor protein (APP). This article briefly reviews the profile of g-secretase inhibitors that have reached the clinic. Studies in both transgenic and nontransgenic animal models of AD have indicated that g-secretase inhibitors, administered by the oral route, are able to lower brain Ab concentrations. However, few data are available on the effects of these compounds on brain Ab deposition after prolonged administration. g-secretase inhibitors may cause abnormalities in the gastrointestinal tract, thymus, spleen, skin, and decrease in lymphocytes and alterations in hair color in experimental animals and in man, effects believed to be associated with the inhibition of the cleavage of Notch, a transmembrane receptor involved in regulating cell-fate decisions. Unfortunately, two large Phase III clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of a detrimental cognitive and functional effect of the drug. The pejorative effects of semagacestat in AD patients may be due to its lack of selectivity on APP processing. The compound could inhibit the processing of one or more substrates of g-secretase important for cognition. It has been also noted that semagacestat causes the accumulation of a neurotoxic peptide (CTFb or C99) resulting from the block of the g-secretase cleavage activity of APP. New more selective g-secretase inhibitors are being developed with the hope of overcoming these limitations.