ABSTRACT
Inflammation has been associated with the two classic lesions in the Alzheimer's (AD) brain, amyloid deposits and neurofibrillary tangles. Recent data suggest that Triflusal, a compound with potent anti-inflammatory effects in the central nervous system in vivo, might delay the conversion from amnestic mild cognitive impairment to a fully established clinical picture of dementia. In the present study, we investigated the effect of Triflusal on brain Abeta accumulation, neuroinflammation, axonal curvature and cognition in an AD transgenic mouse model (Tg2576). Triflusal treatment did not alter the total brain Abeta accumulation but significantly reduced dense-cored plaque load and associated glial cell proliferation, proinflammatory cytokine levels and abnormal axonal curvature, and rescued cognitive deficits in Tg2576 mice. Behavioral benefit was found to involve increased expression of c-fos and BDNF, two of the genes regulated by CREB, as part of the signal transduction cascade underlying the molecular basis of long-term potentiation. These results add preclinical evidence of a potentially beneficial effect of Triflusal in AD.
Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Brain/drug effects , Brain/metabolism , Central Nervous System Agents/pharmacology , Salicylates/pharmacology , Alzheimer Disease/pathology , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/metabolism , Animals , Axons/drug effects , Axons/pathology , Brain/pathology , Brain-Derived Neurotrophic Factor/metabolism , Cognition Disorders/drug therapy , Cognition Disorders/metabolism , Cognition Disorders/pathology , Cytokines/metabolism , Disease Models, Animal , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neuroglia/drug effects , Neuroglia/pathology , Plaque, Amyloid/drug effects , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathology , Proto-Oncogene Proteins c-fos/metabolismABSTRACT
gamma-Secretase is an intramembranous multi-protein complex that cleaves many type-I proteins with critical roles in neuronal function. In Alzheimer's disease (AD) interest in gamma-secretase comes, in part, from the fact that this complex is responsible for the last cleavage step of the amyloid precursor protein (APP) that generates the amyloid-beta peptide (Abeta). Abeta represents the primary component of the amyloid plaque, one of the main pathological hallmarks of AD. Over the last years, considerable efforts have been made to develop drugs to reduce Abeta production with the aim to slow AD progression. Many inhibitors of this protease have been identified, although the clinical use has been limited by concerns about the possible toxicity of these compounds. gamma-secretase inhibitors have been shown to reduce Abeta in vitro and in vivo, but interference with Notch proteolysis causes immunological and gastrointestinal toxicity in animal models. The observation that some nonsteroidal anti-inflammatory drug (NSAID) derivatives are able to specifically lower Abeta42 and the development of inhibitors with Notch-sparing selectivity has revived the interest in gamma-secretase as an attractive target for drug intervention in AD. Despite the fact that all clinical trials with NSAIDs or gamma-secretase modulators in AD have failed to show clinical benefit thus far, the main concern is that the Abeta-lowering potency of the tested compounds may be too low. Active efforts are being made to develop compounds able to penetrate into the brain to lower Abeta at physiological doses without interfering with the cleavage and function of other critical gamma-secretase substrates. These novel inhibitors and modulators may soon offer hope in the Alzheimer's fight.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Protease Inhibitors/therapeutic use , Alzheimer Disease/enzymology , Amyloid Precursor Protein Secretases/chemistry , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Animals , Drug Design , Humans , Protease Inhibitors/chemistry , Protein Conformation , Structure-Activity Relationship , Substrate Specificity , Treatment OutcomeABSTRACT
Amyloid deposits, neurofibrillary tangles, and neuronal cell death in selectively vulnerable brain regions are the chief hallmarks in Alzheimer's (AD) brains. Glycogen synthase kinase-3 (GSK-3) is one of the key kinases required for AD-type abnormal hyperphosphorylation of tau, which is believed to be a critical event in neurofibrillary tangle formation. GSK-3 has also been recently implicated in amyloid precursor protein (APP) processing/Abeta production, apoptotic cell death, and learning and memory. Thus, GSK-3 inhibition represents a very attractive drug target in AD and other neurodegenerative disorders. To investigate whether GSK-3 inhibition can reduce amyloid and tau pathologies, neuronal cell death and memory deficits in vivo, double transgenic mice coexpressing human mutant APP and tau were treated with a novel non-ATP competitive GSK-3beta inhibitor, NP12. Treatment with this thiadiazolidinone compound resulted in lower levels of tau phosphorylation, decreased amyloid deposition and plaque-associated astrocytic proliferation, protection of neurons in the entorhinal cortex and CA1 hippocampal subfield against cell death, and prevention of memory deficits in this transgenic mouse model. These results show that this novel GSK-3 inhibitor has a dual impact on amyloid and tau alterations and, perhaps even more important, on neuronal survival in vivo further suggesting that GSK-3 is a relevant therapeutic target in AD.