. 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. This paper provides solid support for the idea that BDNF can regulate SORLA expression via ERK activation. It presents interesting findings showing that BDNF, acting via SORLA, can decrease Aβ generation in wild-type mice and primary neurons.

    This is a tantalizing finding, as previous studies, including our own, did not see altered Aβ in aged 3xTg-AD mice following neural stem cell treatment, despite the fact that the NSCs produce and elevate levels of BDNF (Blurton-Jones et al., 2009). Another group led by Dr. Mark Tuszynski also did not observe any changes in Aβ in the J20 mouse model following viral BDNF delivery.

    There are a couple of likely explanations for the differences between the effects of BDNF on Aβ generation in the study by Rohe et. al. and our own data:

    Firstly, the concentration of BDNF used by Rohe et al. in vivo (40 ug/hippocampus) is substantially higher than the elevation of BDNF we see in the brain following NSC delivery. We find by ELISA that brain levels of BDNF increase from about 10.5 pg/mg of tissue to 15 pg/mg. That translates to an increase in total brain BDNF from 4.2 ng up to about 6 ng. Thus, the supraphysiological levels of BDNF used in vivo by Rohe et al. may complicate the interpretation of these results. It would be very interesting to know if the converse is true; that is, do mouse Aβ levels decrease in the Huntington model or BDNF knockout mice that they utilized? We think this would more clearly address the physiological effects of BDNF on APP metabolism.

    Another important difference between our findings and the current study is that Rohe et. al. examined the effects of BDNF in wild-type mice. Our study utilized the 3xTg-AD mice, and Dr. Tuszynski's study utilized the J20 line. Both of these transgenic models harbor the Swedish mutation that enhances β-secretase cleavage of APP. Thus, the effects of the Swedish mutation on APP processing might override any influence of BDNF and SORLA that might have driven non-amyloidogenic processing of APP in our study. This suggests that it may be very interesting and important to perform these kinds of experiments in mice that express wild-type human APP.

    Overall, this study adds intriguing information about the possible connections among BDNF, SORLA, and AD. Although we would respectfully argue that studies that examine the effects of more physiologic reduction or elevation of BDNF would help to more precisely define the relationship between BDNF and APP processing in vivo.

    View all comments by Frank LaFerla
  2. 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.


    . 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.

  3. The finding that BDNF reduces Aβ production by regulating the expression of SORLA is a potential link between degeneration of the locus coeruleus (LC), the main source of the neurotransmitter norepinephrine in the limbic system and forebrain, and the development of AD neuropathology. Although it is well established that LC neurons degenerate early in AD, the functional consequences are not well understood. In general, the LC appears to protect against Aβ neuropathology. For example, lesions of the LC enhance Aβ plaque formation in transgenic mice that overexpress mutant APP, a commonly used animal model of AD (Heneka et al., 2006).

    Intriguingly, LC neurons express and release BDNF, and NE itself can promote BDNF expression in target neurons; thus, when LC neurons degenerate early during the early stages of AD, this source of BDNF is lost or greatly reduced. The newly described ability of BDNF to increase SORLA suggests that one consequence of LC degeneration could be a decrease in SORLA expression, leading to dysregulated sorting of Aβ and again resulting in greater amyloid plaque deposition in the LC denervated cortical and hippocampal target sites.

    View all comments by David Weinshenker
  4. 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


    . 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):3571-83. 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.

  5. The article by Rohe et al. presents strong evidence for another unexpected link between SORLA (LR11) and Alzheimer disease. By screening a panel of growth factors, the authors identified BDNF and CTGF as inducers of Sorla transcription. While the paper focuses on BDNF, the induction of Sorla by CTGF is also of great interest and likely to be relevant to the role of SORLA/LR11 in atherosclerosis. In cultures established from Sorla-deficient mice, BDNF signaling through TrkB, ERK, and Akt appeared unaffected, and BDNF stimulation induced APP expression equally well in wild-type and Sorla-deficient neurons. In neuronal cultures from PDAPP mice, BDNF stimulation impressively induced Sorla expression while reducing Aβ40 and Aβ42 by about 50 percent.

    Results from limited in vivo experiments corroborated some of the in vitro findings, and the authors found significant reduction in Aβ40 levels after ventricular infusion of BDNF for seven days. Based on their results, the authors suggest that induction of Sorla may explain the apparently conflicting actions of BDNF in increasing APP expression while antagonizing Aβ production. However, in Sorla-deficient neurons Aβ production was not increased after BDNF treatment, suggesting that other downstream effects of BDNF must influence APP processing in the absence of SORLA. Nevertheless, the unexpected and important observation that SORLA/LR11 expression can be regulated by BDNF and CTGF adds an important new element to understanding the role of this receptor in human diseases.

    This article presents strong evidence for another unexpected link between SORLA (LR11) and Alzheimer disease.

    View all comments by James J. Lah

This paper appears in the following:


  1. Traffic Control: BDNF Boosts SORLA, Reroutes APP
  2. Top AD Trends of 2009