In August 2005, a group of researchers from inside and outside the field of Alzheimer disease met in Bar Harbor, Maine, with foundation and NIH representatives for two days of presentations and discussion at the fifth annual workshop on Enabling Technologies for Alzheimer's Disease Research. The participants sought to identify current knowledge gaps that need to be bridged to provide a foundation for rational therapeutic strategies. They proposed research opportunities for filling these gaps, involving both new technical approaches and fresh ways of looking at old questions. This year's meeting focused on APP function; vascular components of AD and the blood-brain barrier; and mechanisms driving the overlap between aging and AD. The report below is a brief summary of the presentations and discussions, followed by a list of recommendations made by the group. Readers will find a broad description of how open questions in the AD field are evolving, as well as ideas to update their own research programs.
Although a topic of intense interest, it is still not clear what the normal function of APP is and where, when, or why it is processed. Several studies have described a role for APP in controlling neurite outgrowth and cell adhesion, which appears to be activated in the context of the brain's response to injury. Ongoing research investigates a possible role for APP in the migration of newly differentiated neurons to their proper place in the developing cortex. More research is needed to explore the interplay between membrane-bound and soluble fragments of APP and to reconcile seemingly contradictory results in this field.
A fundamental knowledge gap in AD research today is where inside a neuron most Aβ is made. It is clear that Aβ gets deposited in the terminal fields of neurons. Rodent experiments in which the perforant pathway was cut showed subsequent loss of Aβ deposition in the terminal field. These studies are widely considered evidence for APP's axonal transport, processing at the nerve terminal, and presynaptic release of Aβ. However, recent studies exploring a possible physiological role of Aβ in regulating synaptic activity argue that intense neuronal activity drives APP processing to Aβ postsynaptically (Kamenetz et al., 2003). Transecting the perforant pathway would silence its synapses and in this way reduce Aβ release from the postsynaptic side of its terminal field. Reconciling these two views, FRET imaging of presenilin suggests that APP processing may occur near the membrane on both sides of synapses (Tesco et al., 2005).
A physiological role for the processing of APP to Aβ in response to synaptic activity has been suggested by studies demonstrating that Aβ can depress neighboring synapses, thus creating a feedback cycle which could essentially cool down excess synaptic activity. Some data suggest that Aβ causes synaptic depression through a mechanism involving the internalization of excitatory receptors (Synder et al., 2005). Intense research continues to focus on Aβ and the effects of particularly its oligomeric forms on synaptic function. A broad question is how Aβ oligomers affect learning and memory in rodents, and whether they act through a synaptic depression model as just described.
- Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R. APP processing and synaptic function. Neuron. 2003 Mar 27;37(6):925-37. PubMed.
- Tesco G, Ginestroni A, Hiltunen M, Kim M, Dolios G, Hyman BT, Wang R, Berezovska O, Tanzi RE. APP substitutions V715F and L720P alter PS1 conformation and differentially affect Abeta and AICD generation. J Neurochem. 2005 Oct;95(2):446-56. PubMed.
- Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P. Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci. 2005 Aug;8(8):1051-8. PubMed.
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