[Neuroscience] Neuroimmunology and Alzheimers

[John H.]

More Insight Into Alzheimer's Disease With Discovery Of Possible Cause
http://www.sciencedaily.com/releases/2006/11/061120181959.htm
....
Extract
No other researchers had seen this change before, so Tesseur and
Wyss-Coray set out to investigate whether it had some connection to
Alzheimer's disease. They hypothesized that by protecting neurons,
TGF-beta may help prevent Alzheimer's disease. If the TGF-beta pathway
is turned off, the brain becomes more susceptible to a toxic buildup of
proteins.

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TGF beta is turning out to be very important. It suppresses
inflammatory responses and improves non-inflammatory immune responses.
Hence it both boosts and suppresses immune function. Various studies
now indicate widespread deficiencies in vitamin D, this is particularly
true for those in temperate climes and it advisable to increase your
sun exposure during winter to maintain vitamin D production because
vitamin D has a facilitative effect on TGF beta signalling. In some
cases supplements are advisable but wherever possible get out in the
sun. (cf. The UV Advantage, Professor Holick) There was even a Lancet
publication indicating that exposure to sunlight increases serotonin
levels. Hence sunny days makes sunny people, which for us Aussies at
least provides some justification(any justification will do!) for our
"whingeing poms" lament. You don't need that much sun exposure, vitamin
D production is rapid and with the sun there is no risk of over dosing.


The above is very relevant considering that pro-inflammatory cytokines
like tnf a and il 1 are strongly implicated in the pathogenesis of
dementias. Additionally, there is a very strong link between vitamin D
status and Multiple Sclerosis. MS is typically perceived as a Th
1(inflammatory arm) mediated autoimmune disease.

(By the way troops, vitamin D is very important in relation to cancer
prevention.)


It would be interesting to look for linkages of vitamin D, tgf beta,
and TTR(transthyretin). I have seen studies indicating that TTR
facilitates amyloid scavenging. I know of 3 agonist for this: gingko
biloba, nicotine, and short term omega 3 administration. There is good
evidence that astrocytes can scavenge amyloid plaques, possibly by FcR.


Just recently though this fascinating paper below. This is concordant
with the above because:

Cannabinoids are potent antioxidants (cf. Hampson et al, PNAS july 98).

Cannabinoids are anti-inflammatory.
Endogeneous cannabinoids act as retrograde inhibitors so they reduce
calcium influx in the pre synaptic cell and modulate glutamate
transmission, hence possibly conferring some protection against EAA
damage.

Hence, as I have been telling people for years, one good dementia
strategy may be getting stoned once or twice a week. Of course no-one
believed me ... .

Mol. Pharm., ASAP Article 10.1021/mp060066m S1543-8384(06)00066-9
Web Release Date: August 9, 2006
Copyright © 2006 American Chemical Society
A Molecular Link between the Active Component of Marijuana and
Alzheimer's Disease Pathology
Lisa M. Eubanks, Claude J. Rogers, Albert E. Beuscher IV, George F.
Koob, Arthur J. Olson, Tobin J. Dickerson, and Kim D. Janda*
Departments of Chemistry, Immunology, and Molecular Biology, Molecular
and Integrated Neurosciences Department, The Skaggs Institute for
Chemical Biology, and Worm Institute for Research and Medicine, The
Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla,
California 92037
Received June 11, 2006
Abstract:
Alzheimer's disease is the leading cause of dementia among the elderly,
and with the ever-increasing size of this population, cases of
Alzheimer's disease are expected to triple over the next 50 years.
Consequently, the development of treatments that slow or halt the
disease progression have become imperative to both improve the quality
of life for patients and reduce the health care costs attributable to
Alzheimer's disease. Here, we demonstrate that the active component of
marijuana, 9-tetrahydrocannabinol (THC), competitively inhibits the
enzyme acetylcholinesterase (AChE) as well as prevents AChE-induced
amyloid -peptide (A) aggregation, the key pathological marker of
Alzheimer's disease. Computational modeling of the THC-AChE interaction
revealed that THC binds in the peripheral anionic site of AChE, the
critical region involved in amyloidgenesis. Compared to currently
approved drugs prescribed for the treatment of Alzheimer's disease, THC
is a considerably superior inhibitor of A aggregation, and this study
provides a previously unrecognized molecular mechanism through which
cannabinoid molecules may directly impact the progression of this
debilitating disease.
Keywords: Cannabinoids; Alzheimer's disease; acetylcholinesterase