ABSTRACT
Alzheimer's disease (AD) is characterized by progressive memory loss and dementia. The strong correlation between cognitive decline and the loss of synapses supports the idea that synaptic damage is a relevant pathogenic mechanism underlying AD progression. It has been shown that amyloid beta oligomers (AßOs) induce synaptotoxicity ultimately leading to the reduction of dendritic spine density, which underlies cognitive damage. However, the signaling pathways connecting AßOs to synaptic dysfunction have not been completely elucidated. In this review, we have gathered evidence on AßOs receptors and the signaling pathways involved in synaptic damage. We make special emphasis on a new AßOs induced axis that involves the tyrosine kinase ephrin receptor A4 (EphA4) and c-Abl tyrosine kinase activation. EphA4 is a key player in homeostatic plasticity, mediating dendritic spine remodeling and retraction. AßOs aberrantly activate EphA4 leading to dendritic spine elimination. c-Abl is activated in AßOs exposed neurons and in AD patient's brain, and the inhibition of activated c-Abl ameliorates cognitive deficits in AD mouse model. The EphA4 receptor activates c-Abl intracellular signaling. Therefore EphA4 is an emerging AßOs receptor and the activation of the EphA4/c-Abl axis would explain the synaptic spine alterations found in AD.
Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Proto-Oncogene Proteins c-abl/metabolism , Receptor, EphA4/metabolism , Signal Transduction , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Peptides/genetics , Animals , Dendritic Spines/genetics , Dendritic Spines/metabolism , Dendritic Spines/pathology , Humans , Mice , Proto-Oncogene Proteins c-abl/genetics , Receptor, EphA4/genetics , Synapses/genetics , Synapses/metabolism , Synapses/pathologyABSTRACT
The use of natural compounds is an interesting stratagem in the search of drugs with therapeutic potential for the treatment of Alzheimer's disease (AD). We report here the effect of the hyperforin derivative (IDN5706, tetrahydrohyperforin), a semi-synthetic derivative of the St. John's Wort, on the brain neuropathology, learning and memory in a double transgenic (APPswe, PS-1dE9) mouse model of AD. Results indicate that, IDN5706 alleviates memory decline induced by amyloid-beta (Abeta) deposits as indicated by the Morris water maze paradigm. Moreover, the analysis of Abeta deposits by immunodetection and thioflavin-S staining of brain sections, only reveals a decrease in the frequency of the larger-size Abeta deposits, suggesting that IDN5706 affected the turnover of amyloid plaques. Immunohistochemical analysis, using GFAP and n-Tyrosine indicated that the hyperforin derivative prevents the inflammatory astrocytic reaction and the oxidative damage triggered by high Abeta deposit levels. We conclude that the hyperforin derivative, IDN5706, has therapeutic potential for prevention and treatment of AD.
Subject(s)
Alzheimer Disease/drug therapy , Brain/drug effects , Memory Disorders/drug therapy , Phloroglucinol/analogs & derivatives , Terpenes/pharmacology , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/drug effects , Amyloid beta-Peptides/metabolism , Animals , Astrocytes/drug effects , Astrocytes/pathology , Brain/metabolism , Brain/physiopathology , Bridged Bicyclo Compounds/pharmacology , Bridged Bicyclo Compounds/therapeutic use , Disease Models, Animal , Encephalitis/drug therapy , Encephalitis/physiopathology , Encephalitis/prevention & control , Glial Fibrillary Acidic Protein/analysis , Glial Fibrillary Acidic Protein/metabolism , Gliosis/drug therapy , Gliosis/physiopathology , Gliosis/prevention & control , Humans , Maze Learning/drug effects , Maze Learning/physiology , Memory Disorders/metabolism , Memory Disorders/physiopathology , Mice , Mice, Transgenic , Oxidative Stress/drug effects , Oxidative Stress/physiology , Phloroglucinol/pharmacology , Phloroglucinol/therapeutic use , Terpenes/therapeutic use , Tyrosine/analysis , Tyrosine/metabolismABSTRACT
The major protein constituent of amyloid deposits in Alzheimer's disease (AD) is the amyloid beta-peptide (Abeta). In the present work, we have determined the effect of hyperforin an acylphloroglucinol compound isolated from Hypericum perforatum (St John's Wort), on Abeta-induced spatial memory impairments and on Abeta neurotoxicity. We report here that hyperforin: (1) decreases amyloid deposit formation in rats injected with amyloid fibrils in the hippocampus; (2) decreases the neuropathological changes and behavioral impairments in a rat model of amyloidosis; (3) prevents Abeta-induced neurotoxicity in hippocampal neurons both from amyloid fibrils and Abeta oligomers, avoiding the increase in reactive oxidative species associated with amyloid toxicity. Both effects could be explained by the capacity of hyperforin to disaggregate amyloid deposits in a dose and time-dependent manner and to decrease Abeta aggregation and amyloid formation. Altogether these evidences suggest that hyperforin may be useful to decrease amyloid burden and toxicity in AD patients, and may be a putative therapeutic agent to fight the disease.
