Abstract
The efficacy of antihypertensive agents in Alzheimer's disease (AD) is controversial. It has been tested here whether some antihypertensive drugs might influence AD through mechanisms independent of blood pressure-lowering activity. The effects of treatment with the antihypertensive propranolol on cognition and AD-related markers have been studied in the Tg2576 mouse model of AD. Propranolol, at a lower dose than that used as antihypertensive (5 mg/kg, 6 wk), attenuated cognitive impairments shown by Tg2576 mice aged 9 months in the novel object recognition and fear conditioning tests. Propranolol was also able to counteract the increases in hippocampal levels of Aβ(42) present in Tg2576 mice. This effect was accompanied by an increased expression of insulin degrading enzyme. Changes in markers of synaptic pathology, as shown by decreases in phosphorylation of Akt and in the expression of BDNF in Tg2676 mice, were also counteracted by propranolol treatment. Tau hyperphosphorylation shown by Tg2576 mice was also decreased in the hippocampus of propranolol-treated mice, an effect probably related to an increase of GSK3β phosphorylation (inactive form) and a decreased JNK1 expression. Overall, these data further strengthen the potential of propranolol as a therapeutic agent for AD.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Alzheimer Disease / psychology
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism*
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Animals
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Behavior, Animal / drug effects*
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Brain / drug effects*
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Brain / metabolism
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Brain / pathology
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Brain / physiopathology
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Brain-Derived Neurotrophic Factor / metabolism
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Cells, Cultured
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Cognition / drug effects*
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Cognition Disorders / drug therapy*
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Cognition Disorders / genetics
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Cognition Disorders / metabolism
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Cognition Disorders / pathology
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Cognition Disorders / psychology
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Disease Models, Animal
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Fear / drug effects
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Female
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mitogen-Activated Protein Kinase 8 / metabolism
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Motor Activity / drug effects
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Mutation
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Neuronal Plasticity / drug effects
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Peptide Fragments / metabolism
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Phosphorylation
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Propranolol / pharmacology*
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Proto-Oncogene Proteins c-akt / metabolism
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Recognition, Psychology / drug effects
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Signal Transduction / drug effects
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tau Proteins / metabolism*
Substances
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APP protein, human
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Brain-Derived Neurotrophic Factor
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Mapt protein, mouse
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Peptide Fragments
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amyloid beta-protein (1-42)
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tau Proteins
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Propranolol
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 8
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Glycogen Synthase Kinase 3