TWO NEW WAYS IN ALZHEIMER’S DISEASE THERAPY
Alzheimer’s disease (AD), characterized by extracellular and intracellular protein aggregates in neuritic amyloid plaques and neurofibrillary tangles respectively, according amyloid cascade hypothesis, has its primary lesion in the degradation of the amyloid precursor protein (APP) and release of the Aβ42 fragment. Aβ (Amyloid-β) peptides are thought to have a key role in the neurotoxicity and cognitive decline, but there have recently been several disappointments with late-stage clinical trials of new drugs targeting Aβ. Two recent papers shed new light on the molecular mechanisms by which Aβ could cause toxicity and identify targets for new drug development (Du H., et al. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nature Medicine 14, 1097-1105, 2008; Schilling S., et al. Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer’s disease-like pathology. Nature Medicine 14, 1106-1111, 2008).
The team lead by Shi Du Yan (Department of Surgery, College of Physicians and Surgeons, Columbia University, New York) study one of the ways in which Aβ could contribute to the pathogenesis: disruption of mitochondrial function. They found that Aβ interacts with mitochondrial permeability transition pore protein cyclophilin D (CYPD), and their experiments suggest that blocking CYPD could be a useful strategy for reducing Aβ-mediated mitochondrial dysfunction and cognitive decline in AD.
Schilling and his colleagues from Probiodrug AG (Halle, Germany) investigated the production of pyroglutamate (pE)-modified Aβ peptides, which because of their abundance, resistance to proteolysis, rapid aggregation and neurotoxicity, have been suggested as being important in the initiation of pathological cascades resulting in the development of Alzheimer’s disease. They found that pE-modified Aβ peptides was formed by the enzyme glutaminyl cyclase, which inhibition by an orally administered agent, PBD150, resulted in a dramatic improvement in histological and behavioural parameters.
Thus, two new approaches in Alzheimer’s disease therapy might consist in blocking CYPD and glutaminyl ciclase.