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.