. Brain-derived neurotrophic factor reduces amyloidogenic processing through control of SORLA gene expression. J Neurosci. 2009 Dec 9;29(49):15472-8. PubMed.

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  1. The article by Rohe and colleagues presents data derived from in vivo and in vitro studies demonstrating a novel role for brain-derived neurotrophic factor (BDNF) in the induction of SORLA, which regulates intracellular trafficking and processing of APP into Aβ, via the ERK pathway. Despite the caveat that several of the findings presented to support this concept were derived from cultured primary cortical neurons from newborn mice—which are more indicative of developmental processes—evidence is also presented showing that BDNF acts as a physiological inducer of SORLA in a transgenic AD model of amyloidosis. Taken together, these findings lend support for the translation of their data to the actual disease state.

    According to the findings of the Wilnow group, the induction of SORLA gene transcription may be part of the normal actions of BDNF in the brain. How are these proteins affected in AD? Cortical SORLA levels are reduced to a greater extent in those people with MCI who display a more pronounced cognitive impairment (Sager et al., 2007). Both BDNF protein and mRNA are decreased in the cortex and hippocampus beginning at the prodromal stages of AD (Peng et al., 2005). What would be the consequences of the concurrent down regulation of these proteins early in the onset of AD? One possible outcome may be the loss of the inhibitory role of BDNF on APP processing to Aβ, culminating in increased plaque formation in the brain during the development of AD. Hence, elucidating the mechanisms underlying BDNF reductions in the cortex and hippocampus may uncover a pathogenic pathway causing a double-hit in incipient AD: the loss of survival signaling via reduced neurotrophin receptor stimulation and the gain of toxic amyloid accumulation via SORLA downregulation.

    References:

    . Neuronal LR11/sorLA expression is reduced in mild cognitive impairment. Ann Neurol. 2007 Dec;62(6):640-7. PubMed.

    . Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer's disease. J Neurochem. 2005 Jun;93(6):1412-21. PubMed.

  2. We would like to comment on two aspects raised by the interesting paper by Rohe et al. (1), which elegantly shows that BDNF can control the amyloidogenic processing of APP by regulating the expression of SORLA. This pathway of regulation suggests that the expression of SORLA, a protein that controls a trafficking event—that of APP—could be itself controlled by another trafficking event, i.e., the axonal transport of BDNF.

    This brings us to the hotly debated question of whether abnormal axonal transport is a cause, a contributing factor, or a consequence of the pathology in Alzheimer disease (2). The study by Rohe et al. (1) certainly points to the possibility that an impeded axonal transport of BDNF—described as a possible pathogenic factor in several neurodegenerative diseases—could lead to increased amyloidogenic processing of APP, through the downregulation of SORLA. Deficient transport of BDNF has in fact been proposed to occur in Huntington disease (3,4).

    In AD, BDNF levels are reduced (5-7), and it is possible that this is also a result of reduced transport of BDNF.

    In view of the present study, in all neurological disorders where BDNF trafficking is impeded, APP metabolism could—in principle—also be altered. If Rohe et al. (1) are correct, one could expect that APP is abnormally processed, in relevant brain regions, in all neurodegenerative disorders where the levels of BDNF are reduced.

    We would also like to draw attention to the equally interesting comment by David Weinshenker, which points to the possibility that a deficient release of BDNF from locus ceruleus (LC) neurons could lead to increased production of Aβ in remote brain regions (e.g., hippocampus, cortex), where the LC neurons project. We have recently proposed that LC neurons could also provide the seed of aggregated Aβ that may nucleate the formation of the neuritic plaques in lesion-prone regions (8,9).

    Interesting, in this way, the LC neurons could not only provide the seeds, but also trigger the generation of the soluble Aβ that aggregates into plaques. Thus, the AD pathology in the LC may not be a secondary event caused by Aβ poisoning of the projections of LC neurons. The deficiency of LC neurons, which—as pointed out by David Weinshenker—occurs early in AD (see also [10]), could be a cause and a facilitating factor rather than a consequence of the pathology in the lesion-prone brain regions.

    See also:

    Muresan, Z. and V. Muresan, Brainstem Neurons Are Initiators of Neuritic Plaques. SWAN Alzheimer Knowledge Base. Alzheimer Research Forum

    References:

    . Brain-derived neurotrophic factor reduces amyloidogenic processing through control of SORLA gene expression. J Neurosci. 2009 Dec 9;29(49):15472-8. PubMed.

    . Is abnormal axonal transport a cause, a contributing factor or a consequence of the neuronal pathology in Alzheimer's disease?. Future Neurol. 2009 Nov 1;4(6):761-773. PubMed.

    . Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation. J Neurosci. 2007 Mar 28;27(13) PubMed.

    . Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell. 2004 Jul 9;118(1):127-38. PubMed.

    . Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13594-9. PubMed.

    . Stage-dependent BDNF serum concentrations in Alzheimer's disease. J Neural Transm. 2006 Sep;113(9):1217-24. PubMed.

    . Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer's disease. J Neurochem. 2005 Jun;93(6):1412-21. PubMed.

    . Seeding neuritic plaques from the distance: a possible role for brainstem neurons in the development of Alzheimer's disease pathology. Neurodegener Dis. 2008;5(3-4):250-3. PubMed.

    . Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci. 2006 Feb 1;26(5):1343-54. PubMed.

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