Amyloid beta and Amyloid Precursor Protein (APP) modulate the function of central synapses in brain

This is Part 4 of the unabridged original manuscript, submitted by invitation in April 2009 to the theme issue of The Journal of Alzheimer's disease. Edited by the Journal edition was later published and is available upon request (will be published here at a later date)

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Alexei Koudinov, Elena Kezlya, Natalia Koudinova, Temirbolat Berezov Amyloid-beta, tau protein, and oxidative changes as a physiological compensatory mechanism to maintain CNS plasticity under Alzheimer's disease and other neurodegenerative conditions. Journal of Alzheimer’s Disease. 2009 18(2): 381-400. Unabridged Notedited Original Author Edition. Available at: http://alzheimercode.blogspot.com

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Amyloid beta and Amyloid Precursor Protein (APP) modulate the function of central synapses in brain

There are many articles reporting on amyloid beta role in modulating synaptic function [[reviewed in Ref. 17]]. In quoted above article by Malinow group of Cold Spring Harbor [[21, 43]] researchers found that evoked activity of neurons in hippocampal slices stimulated the production of Aβ. This happened primarily by an increased trafficking of APP towards beta secretase sites at the cell membrane. In addition of the increased Aβ formation, there could be an increase of the production of other APP derivates, such as AICD which could also modulate synaptic activity. It is well possible [[44]], that at “physiological expression levels of APP, this provided a negative feedback, since Abeta depresses synaptic activity. Without such depression, synaptic activity could become excessive, leading to excitotoxicity. Indeed, gamma secretase inhibition led to increased EPSC frequency [[21]], and kainate-induced seizures are potentiated in APP knockout mice [[45]]. Further to these studies, a recent report indicated that specific stimulation of NMDA receptors up-regulated APP, inhibited alpha-secretase activity and promoted amyloid beta production [[46]]. Collectively, these studies argue strongly that APP processing, and the presence of amyloid beta itself, are closely associated with synaptic activity and may serve to provide physiological control of activity, guarding against excessive glutamate release” [[44]].

Most recently it was show, that endogenous secreted APP-alpha regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory [[47]]. Specifically, “intrahippocampal infusion of antibodies targeted to endogenous sAPP alpha reduced long-term potentiation (LTP) in the dentate gyrus of adult rats by approximately 50%. Conversely, infusion of recombinant sAPP alpha dose-dependently increased LTP and facilitated in vitro tetanically evoked NMDA receptor-mediated currents. Pharmacological inhibition of alpha-secretase and other alpha-disintegrin-and-metalloproteases by TAPI-1 reduced both LTP and tetanus-evoked NMDA receptor-mediated currents in dentate granule cells. Both effects were prevented by co-application of exogenous recombinant sAPP alpha. Similarly, spatial memory was inhibited by intrahippocampal TAPI-1, an effect that was prevented by co-application of recombinant sAPP alpha” [[47]].

References:

17. AR. Koudinov, TT. Berezov. Alzheimers amyloid-beta (Abeta) is an essential synaptic protein, not neurotoxic junk. Acta Neurobiologica Exp. (2004) 64(1): 71-79.

21. F. Kamenetz, T. Tomita, H. Hsieh, G. Seabrook, D. Borchelt, T. Iwatsubo, S. Sisodia, R. Malinow. APP processing and synaptic function. Neuron (2003) 37:925-937


43. FR. Kamenetz, T. Tomita, DR. Borchelt, SS. Sisodia, T. Iwatsubo, R. Malinow. Activity dependent secretion of beta-amyloid: roles of beta-amyloid in synaptic transmission. Soc. Neurosci. Abstr. (2000) 26: 491.

44. HA. Pearson, C. Peers. Physiological roles for amyloid β peptides. J. Physiol. (2006) 15: 5–10.

45. JP. Steinbach, U. Muller, M. Leist, ZW. Li, P. Nicotera, A Aguzzi. Hypersensitivity to seizures in beta-amyloid precursor protein deficient mice. Cell Death Differ. (1998) 5:858–866.

46. S. Lesne, C. Ali, C. Gabriel, N Croci, ET. MacKenzie, CG. Glabe, M. Plotkine, C. Marchand-Verrecchia, D. Vivien, A. Buisson. NMDA receptor activation inhibits alpha-secretase and promotes neuronal amyloid-beta production. J. Neurosci. (2005) 25:9367–9377.

47. CJ. Taylor. Endogenous secreted amyloid precursor protein-alpha regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory. Neurobiol. Dis. (2008) (2):250-260.

Link to this publication: amyloid-beta-is-needed-for-synapse

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