title: A brief, but repeated, swimming protocol is sufficient to overcome amyloid beta-protein inhibition of hippocampal long-term potentiation.
abstract: Alzheimer's disease starts as an almost imperceptible malady, first observed clinically as a mild memory problem. Accumulating genetic and biochemical data have suggested that amyloid beta-protein (Abeta) plays an important role in this memory loss, and Abeta has been shown to suppress long-term potentiation (LTP), a cellular model for memory and learning. Here we show that a very brief (3 min) swimming, twice daily for 2 weeks, rescues LTP inhibition in the CA1 region of hippocampal slices caused by Abeta(42) or Abeta(40) carrying the Arctic mutation using a theta burst stimulation (TBS) protocol. Whereas the input-output curve was not affected, the paired-pulse ratio was reduced in mice receiving our repeated swimming protocol, suggesting a possible involvement of presynaptic facilitation. Similar to swimming, Abeta's inhibition of LTP could be rescued with the adenylyl cyclase, forskolin. Interestingly, this swimming protocol produced conditions in which a weak-TBS could invoke LTP not observed in naïve mice, which again was mimicked by forskolin. In contrast, the protein kinase A (PKA) inhibitor, H89, blocked both the forskolin and swimming potentiation of LTP; these data implicate cAMP/PKA signaling in the protective effect of swimming and mediating Abeta' detrimental effects. Our data add a new simple behavior paradigm that shows the importance of an environmental factor in reversing the pathophysiological effects of Abeta, and suggest new therapeutic avenues.
authors.affiliation: Department of Biochemistry, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA.
authors.forename: Shaomin
authors.initials: S
authors.lastname: Li
authors.forename: Larry A
authors.initials: LA
authors.lastname: Feig
authors.forename: Dean M
authors.initials: DM
authors.lastname: Hartley
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D005576:Colforsin / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005260:Female; D006624:Hippocampus / Q000187:drug effects*; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D008297:Male; D051379:Mice; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013550:Swimming; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D007546:Isoquinolines; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C078592:amyloid beta-protein (1-40); D005576:Colforsin; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide