Cortisol, I believe, inhibits BDNF expression or function. Fatty diet (low in Essential Fatty Acids-EFA) causes permanent stress in the offspring--with raised cortisol and homocysteine--when consumed in pregnancy. Fatty adult diet causes mitochondrial uncoupling, impaired ATP formation and superoxide production, by depleting mit. membranes of EFA. There are large unexplained variations in Huntington's onset and severity, which may be explained by the above observations. I have seen HD develop in the 40-year old anxious, fat-eating daughter of a calmer mother, who developed HD at a later stage of life, and progressed more slowly. Nutritionally, the best intervention for HD--until some cure for the genetic fault comes along--would be to institute low-fat, EFA rich diet, and if anxiety is present, add 10 gm daily of Inositol powder supplement, which should lower the cortisol and homocysteine levels, thus improving BDNF function etc.. It wouldn't hurt to throw in some folic acid. Dr Krishna Vaddadi, in far-off Australia, has used EFA with good results. Nobody has yet tried Inositol,...  Read more

Cortisol, I believe, inhibits BDNF expression or function. Fatty diet (low in Essential Fatty Acids-EFA) causes permanent stress in the offspring--with raised cortisol and homocysteine--when consumed in pregnancy. Fatty adult diet causes mitochondrial uncoupling, impaired ATP formation and superoxide production, by depleting mit. membranes of EFA. There are large unexplained variations in Huntington's onset and severity, which may be explained by the above observations. I have seen HD develop in the 40-year old anxious, fat-eating daughter of a calmer mother, who developed HD at a later stage of life, and progressed more slowly. Nutritionally, the best intervention for HD--until some cure for the genetic fault comes along--would be to institute low-fat, EFA rich diet, and if anxiety is present, add 10 gm daily of Inositol powder supplement, which should lower the cortisol and homocysteine levels, thus improving BDNF function etc.. It wouldn't hurt to throw in some folic acid. Dr Krishna Vaddadi, in far-off Australia, has used EFA with good results. Nobody has yet tried Inositol, which requires the insight to detect chronic anxiety, the best marker for which is probably a history of shyness in childhood.

View all comments by Robert Peers

I find this paper a significant contribution to the field, and one that will undoubtedly engender further work and exploration into potential new therapeutics. This is important for the Alzheimer's field because new approaches designed to increase vesicular transport may significantly aid Alzheimer's victims. Specifically:

It is interesting to find decreased BDNF transport in Huntington's disease, in view of the decrease in BDNF transcription that was previously reported (Zuccato et al., 2001) and which presumably occurs via polyglutamine-mediated interference with CBP-regulated gene transcription (Nucifora et al., 2001). Importantly, as Gauthier et al. note in their current manuscript, these two mechanisms are not mutually exclusive and could both contribute to neuronal death.

The parallels that we and others find with decreased BDNF transcription in cortex and hippocampus of Alzheimer's disease (  Read more

I find this paper a significant contribution to the field, and one that will undoubtedly engender further work and exploration into potential new therapeutics. This is important for the Alzheimer's field because new approaches designed to increase vesicular transport may significantly aid Alzheimer's victims. Specifically:

It is interesting to find decreased BDNF transport in Huntington's disease, in view of the decrease in BDNF transcription that was previously reported (Zuccato et al., 2001) and which presumably occurs via polyglutamine-mediated interference with CBP-regulated gene transcription (Nucifora et al., 2001). Importantly, as Gauthier et al. note in their current manuscript, these two mechanisms are not mutually exclusive and could both contribute to neuronal death.

The parallels that we and others find with decreased BDNF transcription in cortex and hippocampus of Alzheimer's disease (Garzon et al., 2002; Holsinger et al., 2000; Murray et al., 1994; Phillips et al., 1991) suggest BDNF downregulation as a general mechanism for compromising neuronal survival in neurodegenerative diseases.

Decreases in NGF in nucleus basalis of Alzheimer's disease patients and increases in proNGF in cortex and hippocampus (Scott et al., 1995; Hock et al., 2000; Fahnestock et al., 2001) are also consistent with a defect in cholinergic basal forebrain neuronal transport of neurotrophic factors in Alzheimer's disease.

ProBDNF is decreased in Alzheimer's disease (Michalski and Fahnestock, 2003), and we are examining retrograde transport of proNGF and proBDNF. The potential involvement of proBDNF should also be examined in Huntington's disease, particularly in light of the demonstrated involvement of the pro domain in activity-dependent secretion of BDNF (Egan et al., 2003).

View all comments by Margaret Fahnestock

The findings of decreased BDNF transport in Huntington's disease, as well as the reports by the Brady and Goldstein groups are significant, as they support the hypothesis that various neurodegenerative disorders display impaired axonal transport defects. These findings parallel the findings from our group showing a deficit in the retrograde transport of NGF within the cholinergic basal forebrain cortical projection system, a reduction in cortical levels of the NGF signal transduction trkA receptor, as well as decreased pre and proBDNF transcription in cortex and hippocampus during the progression of Alzheimer's disease.

These obsersvation lends support to the emerging concept that several of the most common human neurodegnerative diseases have a common underlying defect in impaired axonal transport in addition to the more traditional pathologic lesions. Transport defects may play pivotal roles in the selective vulnerability of neuronal populations leading to cell death.

Reference:
Peng S, Wuu J, Mufson EJ, Fahnestock M. Increased proNGF levels in subjects with...  Read more

The findings of decreased BDNF transport in Huntington's disease, as well as the reports by the Brady and Goldstein groups are significant, as they support the hypothesis that various neurodegenerative disorders display impaired axonal transport defects. These findings parallel the findings from our group showing a deficit in the retrograde transport of NGF within the cholinergic basal forebrain cortical projection system, a reduction in cortical levels of the NGF signal transduction trkA receptor, as well as decreased pre and proBDNF transcription in cortex and hippocampus during the progression of Alzheimer's disease.

These obsersvation lends support to the emerging concept that several of the most common human neurodegnerative diseases have a common underlying defect in impaired axonal transport in addition to the more traditional pathologic lesions. Transport defects may play pivotal roles in the selective vulnerability of neuronal populations leading to cell death.

Reference:
Peng S, Wuu J, Mufson EJ, Fahnestock M. Increased proNGF levels in subjects with mild cognitive impairment and mild Alzheimer disease. J Neuropathol Exp Neurol. 2004 Jun ;63(6):641-9. Abstract

View all comments by Elliott Mufson

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...  Read more

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 Mathew Blurton-Jones
View all comments by Frank LaFerla

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...  Read more

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

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...  Read more

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