Still more research needed but here's an example where the symptoms were treated without targeting the amyloids.
I wonder if the BDNF made the neurons stronger or enhanced their ability to communicate, and thus helped reduce the cognitive impairment. [...] Maintaining proper functions with a dwindling number of neurons is great progress, but more optimal would be to keep as many neurons as possible and get rid of the amyloid-beta.
Right but the key point is that simply removing the amyloids alone may not be sufficient to treat the ravages of aging. There's still a lot that needs to be flushed out here but upgregulating the neurotrophic factors seems to be the more effective measure according to this paper.
I think that it's uncontroversial "that simply removing the amyloids alone may not be sufficient to treat the ravages of aging": just confining ourselves to the brain, we also need to remove NFTs and a range of other intracellular and lysosomal inclusions, obviate mitochondrial mutations, and replace existing and inevitable occasional ongoing cell loss; moreover, the brain is of course affected by the systemic effects of aging elsewhere in the body on redox tone and inflammation, so to fully rejuvenate the brain will entail fully rejuvenating the rest of the body. But I think that the idea that an agent to protect cells from the toxic effects of aging damage is ultimately superior to
repairing that damage is somewhat implausible on its face: certainly, BDNF might be a good short-term, stopgap measure, but it can only reduce the damaging effects, not eliminate them, whereas removing the underlying damage removes the secondary effects of that damage
gratis. Moreover, as Aubrey regularly emphasizes, dynamic metabolic pathways like the ones regulating BDNF are 'set' where they are
for a reason, and overriding those regulatory pathways inevitably carries risks; in the case of boosting BDNF, the most obvious one would be cancer, since many cancers (including, in particular, neuroblastomas in the brain) exploit the BDNF signaling pathway to help them resist apoptotic signaling and increase needed vascularization:
The neurotrophic receptor tyrosine kinase TrkB, while binding its high affinity ligand brain-derived neurotrophic factor (BDNF), will play an essential role for nervous system development, neuronal survival, differentiation, and maintenance. However, accumulating evidences implies that TrkB signal pathway may also be involved in a variety of human cancers, in which TrkB is likely to play a role in initiation and metastasis of carcinomas. Overexpression of TrkB is often correlated with the tumorigenesis, angiogenesis and drug resistance in these malignancies, contributing significantly to the metastasis and aggressive phenotype of these poor prognosis tumors. The evidences to show the significant contribution of TrkB to malignancy not only came from solid tumors such as neoblastoma, pancreas cancer, Wilm's tumor and hepatocarcinoma, but also came from haematological malignancies ... Emerging data have suggested that TrkB may be a mediator as well as a marker of carcinogenesis and metastasis, therefore TrkB may be used as a valuable target for cancer therapy especially for the metastatic tumors with poor prognosis.(1)
TRK-B encodes a tyrosine kinase that binds to brain-derived neuotrophic factor (BDNF), as well as neurotrophin-3 (NT-3) and NT-4/5. We have studied the N-myc-amplified human neuroblastoma cell line, SMS-KCN, which expresses both TRK-B and BDNF. Exogenous BDNF induces tyrosine phosphorylation of TRK-B ... In addition, BDNF appears to promote cell survival and neurite outgrowth. ... [Of] a series of 74 primary neuroblastomas, 36% express TRK-B mRNA, 68% express BDNF mRNA, and 31% express both. Truncated TRK-B appears to be preferentially expressed in more-differentiated tumors (ganglioneuromas and ganglioneuroblastomas), whereas full-length TRK-B is expressed almost exclusively in immature neuroblastomas with N-myc amplification. Our findings suggest that in TRK-B-expressing human neuroblastomas, BDNF promotes survival and induces neurite outgrowth in an autocrine or paracrine manner. The BDNF/TRK-B pathway may be particularly important for growth and differentiation of neuroblastomas with N-myc amplification.(2)
I also think that there's been some confusion on one particular point:
upgregulating the neurotrophic factors seems to be the more effective measure according to this paper.
They actually don't say anything to indicate that; I think that you misunderstood the import of one passage (and, actually, the researchers themselves may also not have been thinking clearly on the point):
The protective and restorative effects of BDNF occurred in the mice, independent of the amount of amyloid deposited.
This is an important finding because it suggests, as a lot of research has suggested, that amyloid may not be the primary cause of behavior problems that you see in Alzheimer patients, said Elliott Mufson, PhD, Rush University Professor of Neurological Sciences, who was not affiliated with the Nature Medicine study.
Dr. Koliatsos agreed, noting that this comes at a time when amyloid, the predominant target of therapy for Alzheimer disease, has not given us great therapeutic products or solutions.
On that first bit, (a) the fact that BDNF is effective "independent of the
amount of amyloid deposited" isn't evidence that Abeta isn't a major contributor to AD, or that its removal isn't central to its arrest and ultimate reversal; rather, it's again evidence for what has actually been the dominant model for much of the last decade: that the smaller, soluble oligomeric Abeta species, rather than the deposited, fibrillar plaque, is the critical Abeta species (though the plaque is unlikely to be helpful except as a dispensible 'sink'). Similarly on the alpha-secretase experiment:
Mechanisms That Prevent Alzheimer's Disease: Enzymatic Activity Plays Key Role.
[Scientists] have succeeded in gaining further insight in the functioning of endogenous mechanisms that protect against the development of Alzheimer's disease. It was found that the activity of the enzyme α-secretase is mainly responsible for the protective effect. ...
"The α-secretase enzyme is a highly complex one, with many other functions. For example, it also relays signals from the intercellular space into cells and interacts with molecules on other cells." Fahrenholz and his colleagues have now established, following investigations in a transgenic mouse model, that it is the enzymatic activity alone that guarantees the protective effects. If this activity is neutralised, the laboratory mice exhibit the symptoms that are characteristic of Alzheimer's disease: impaired learning ability, poor memory capacity and the build-up of Aβ plaques. It is thus possible that the enzymatic activity of α-secretase could represent the starting point for the development of future treatments.
At the same time, the researchers were able to confirm with their experiments that it is not the plaque build-up itself that is responsible for the loss of memory capacity. The cytotoxic substances that accumulate in plaques only destroy neuron synapses when they are still in solution. Prof. Fahrenholz concludes: "It is important to consider other aspects in addition to the plaques themselves, particularly their precursors, which are a real cause of the disease."
That is a fairly bold statement ("real cause"), but more data is pointing to at least a combination of things responsible for Alzheimer's not just the A-beta plaque.
Again, Fahrenholz is in no way saying that his results imply the irrelevance of Abeta, but that Abeta species "only destroy neuron synapses
when they are still in solution" -- that "in addition to
the plaques themselves, " "
their precursors, which are
a [not, NB, "
the" -MR] real cause of the disease."
Indeed, as the press article indicates, what's happening here is that it's not some external effect of alpha-secretase that gives the enzyme its protective effect, but "the
activity of the enzyme α-secretase [that] is mainly responsible for the protective effect." "The activity" is the cleavage of amyloid precursor protein (APP/betaAPP) into various physiological signaling molecules; this denies APP as a precursor to beta-secretase (BACE), so that "If this activity is neutralised, the laboratory mice exhibit the symptoms that are characteristic of Alzheimer's disease ... [including] the build-up of Aβ plaques".
It's also certainly true that when alpha-secretase's production of
its normal physiological products is impaired, this in itself will have negative effects on brain structure and function, contributing to the progression of the disease; one mechanism of such denial appears to be (wait for it) the upregulation of BACE activity by aggregation-prone Abeta species (Abeta42):
HEK293 cells overexpressing wild-type betaAPP exhibit a DFK167-sensitive increase in BACE1 promoter transactivation that is increased by the Abeta-potentiating Swedish mutation. This effect was mimicked by exogenous application of Abeta42 but not Abeta40 or by transient transfection of cDNA encoding Abeta42 sequence. ... Furthermore, APP/beta-amyloid precursor protein-like protein deficiency does not affect BACE1 activity and expression. Overall, these data suggest that physiological levels of endogenous Abeta are not sufficient per se to modulate BACE1 promoter transactivation but that exacerbated Abeta production ... modulates BACE1 promoter transactivation and activity via an NFkappaB-dependent pathway. (3)
As to (b) the
op cit comments of Drs. Mufson and Koliatsos: this is in my view hyperbolic at best. In particular, to say that the new study "comes at a time when amyloid, the predominant target of therapy for Alzheimer disease, has not given us great therapeutic products or solutions" is really not very helpful: Abeta removal strategies are only now getting into Phase III trials, so it's hardly reasonable to complain that they haven't delivered yet. (Cf the much more egregious -- indeed, completely disingenuous -- example of embryonic stem cells, whose less-ethical bioconservative opponents complain "haven't cured any diseases," while we have a zillion "therapies" (nearly all of which amount to bone marrow transplant) available now from adult stem cells. Of course, we only first even
cultured ESCs a decade ago, and they've been under political constraints and market uncertainty almost from the first day of their derivation; indeed, the people sneering "no cures!" are the very same people pushing for restrictions on developing those cures, while the "adult stem cells" they're touting are largely haematopoietic stem cells, on which we've enjoyed forty years of unrestricted research and clinical experience.
-Michael
References1: Han L, Zhang Z, Qin W, Sun W. Neurotrophic receptor TrkB: Is it a predictor of
poor prognosis for carcinoma patients? Med Hypotheses. 2007;68(2):407-9. Epub
2006 Sep 27. PubMed PMID: 17008023.
2. Nakagawara A, Azar CG, Scavarda NJ, Brodeur GM.
Expression and function ofTRK-B and BDNF in human neuroblastomas. Mol Cell Biol. 1994 Jan;14(1):759-67.
PubMed PMID: 8264643; PubMed Central PMCID: PMC358424.
3. : Buggia-Prevot V, Sevalle J, Rossner S, Checler F.
NFkappaB-dependent controlof BACE1 promoter transactivation by Abeta42. J Biol Chem. 2008 Apr
11;283(15):10037-47. Epub 2008 Feb 8. PubMed PMID: 18263584.
