DHA reduces pathology of Alzheimer's in mouse study

shimuhy · medicine forum beginner Joined: 06 Oct 2005 Posts: 10

It has been shown by epidemiological studies that increased intake of
the omega-3 (n-3) polyunsaturated fatty acid (PUFA) docosahexaenoic
acid (DHA) associates with reduced risk of Alzheimer's disease.

In a new study published in the Journal of Neuroscience, by using a
transgenic mouse model of Alzheimer's, researchers found evidence that
DHA-enriched diets may protect against beta-amyloid production,
accumulation, and potential downstream toxicity associated with
pathology of Alzheimer's.

In another study published in the journal Neuron, researchers from the
same group have discovered that DHA protects against dendritic
pathology in an Alzheimer's disease mouse model.

More at:
http://www.webmedtoday.com/advmedsci/Aging/Aging0508016.htm
http://www.webmedtoday.com/forum/viewtopic.php?t=361

montygram · medicine forum Guru Joined: 30 Apr 2005 Posts: 825

If you listen to epidemiologists, you will eventually feel like a ping
pong ball. They could find an "association" between any two things in
the universe, and most of them no next to nothing of biochemistry.
When you take DHA supplements, you change the danger from one form to
another (see the abstract below). DHA and arachidonic acid interfere
with each other, and that is the "benefit" most of these studies are
noting. Just avoid any major source of dietary polyunsaturated fatty
acids and you'll save yourself a huge amount of suffering.

Brain Pathol. 2005 Apr;15(2):143-8.

The biochemistry of the isoprostane, neuroprostane, and isofuran
Pathways of lipid peroxidation.

Roberts LJ 2nd, Fessel JP, Davies SS.

Department of Pharmacology, 522 RRB, Vanderbilt University, Nashville,
TN 37232-6602, USA. jack.roberts@vanderbilt.edu

Isoprostanes are prostaglandin-like compounds that are formed
non-enzymatically by free radical-catalyzed peroxidation of arachidonic
acid (C20:4omega6). Intermediates in the pathway of the formation of
isoprostanes are labile prostaglandin H2-like bicyclic endoperoxides
(H2-isoprostanes). H2-isoprostanes are reduced to form F-ring
isoprostanes (F2-isoprostanes), but they also undergo chemical
rearrangement in vivo to form E2- and D2-isoprostanes, isothromboxanes,
and highly reactive acyclic y-ketoaldehdyes (isoketals). E2- and
D2-isoprostanes also undergo dehydration in vivo to form cyclopentenone
A2- and J2-isoprostanes. Docosahexaenoic acid (C22:6omega3) is highly
enriched in neurons in the brain and is highly susceptible to
oxidation. Free radical-catalyzed oxidation of docosahexaenoic acid
results in the formation of isoprostane-like compounds
(neuroprostanes). F4-, D4-, E4-, A4-, and J4-neuroprostanes and
neuroketals have all been shown to be produced in vivo. In addition, we
recently discovered a new pathway of lipid peroxidation that forms
compounds with a substituted tetrahydrofuran ring (isofurans). Oxygen
concentration differentially modulates the formation of isoprostanes
and isofurans. As oxygen concentrations increase, the formation of
isofurans is favored whereas the formation of isoprostanes becomes
disfavored.

montygram · medicine forum Guru Joined: 30 Apr 2005 Posts: 825

A couple more good ones are below. Remember, it's not just about
substances - it's about stress and substances. In the case of
arachidonic acid, epa, and dha, a little stress causes dangerous
metabolites to be synthesizesd because these molecules are so
biochemically unstable.

Biochemistry. 2002 Sep 24;41(3 Cool

:11466-71.

Identification of oxidized derivatives of neuroketals.

Bernoud-Hubac N, Roberts LJ 2nd.

Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
37232-6602, USA.

Oxidative stress and protein aggregation have been implicated in the
pathogenesis of neurodegenerative diseases. The formation of
neuroprostanes, isoprostane-like compounds formed from oxidation of
docosahexaenoic acid, which is uniquely enriched in the brain, is
increased in Alzheimer's disease. We recently identified the formation
of a new class of highly reactive gamma-keto aldehydes, neuroketals, in
vivo as products of the neuroprostane pathway. Neuroketals adduct to
lysine residues of proteins with remarkable rapidity and induce
cross-linking. Because neuroketals have either a 1,4-pentadiene or
1,4,7-octatriene side chain structure, we hypothesized that they could
undergo further oxidation to form neuroketals with an additional
hydroxyl group. Oxidation of docosahexaenoic acid in vitro yielded a
series of compounds that were confirmed to be oxidized neuroketals by
mass spectrometric analyses. Analysis of oxidized neuroketal adducts
during oxidation of docosahexaenoic acid in the presence of lysine
revealed the formation of oxidized Schiff base and hydroxylactam
adducts. Oxidized hydroxylactam neuroketal-lysyl protein adducts,
analyzed after digestion of proteins to individual amino acids, were
not detected in nonoxidized rat brain synaptosomes but were readily
detected following oxidation of synaptosomes. These studies indicate
that neuroketals can undergo further oxidation, which in turn suggests
that measurement of only unoxidized neuroketal adducts likely
underestimates the amount of neuroketal adducts present in the brain in
disorders of oxidant stress.

J Biol Chem. 1998 May 29;273(22):13605-12.

Formation of isoprostane-like compounds (neuroprostanes) in vivo from
docosahexaenoic acid.

Roberts LJ 2nd, Montine TJ, Markesbery WR, Tapper AR, Hardy P, Chemtob
S, Dettbarn WD, Morrow JD.

Departments of Pharmacology, Pathology, and Medicine, Vanderbilt
University, Nashville, Tennessee 37232, USA.
jack.roberts@mcmail.vanderbilt.edu

F2-isoprostanes are prostaglandin F2-like compounds that are formed
nonenzymatically by free radical-induced oxidation of arachidonic acid.
We explored whether oxidation of docosahexaenoic acid (C22:6omega3),
which is highly enriched in the brain, led to the formation of
F2-isoprostane-like compounds, which we term F4-neuroprostanes.
Oxidation of docosahexaenoic acid in vitro yielded a series of
compounds that were structurally established to be F4-neuroprostanes
using a number of mass spectrometric approaches. The amounts formed
exceeded levels of F2-isoprostanes generated from arachidonic acid by
3.4-fold. F4-neuroprostanes were detected esterified in normal whole
rat brain and newborn pig cortex at a level of 7.0 +/- 1.4 ng/g and
13.1 +/- 8 ng/g, respectively. Furthermore, F4-neuroprostanes could be
detected in normal human cerebrospinal fluid and levels in patients
with Alzheimer's disease (110 +/- 12 pg/ml) were significantly higher
than age-matched controls (64 +/- 8 pg/ml) (p < 0.05).
F4-neuroprostanes may provide a unique marker of oxidative injury to
the brain and could potentially exert biological activity. Furthermore,
the formation of F4-neuroprostane-containing aminophospholipids might
adversely effect neuronal function as a result of alterations they
induce in the biophysical properties of neuronal membranes.

montygram · medicine forum Guru Joined: 30 Apr 2005 Posts: 825

I had been taking fish oil supplements for over a year before I lost
the ability to digest and absorb food (probably protein mostly), and
the following should put a scare into those who think these unstable
substances are anything but recipes for disaster:

FASEB J. 2002 May;16(7):715-7. Epub 2002 Mar 12.

Effects of reactive gamma-ketoaldehydes formed by the isoprostane
pathway (isoketals) and cyclooxygenase pathway (levuglandins) on
proteasome function.

Davies SS, Amarnath V, Montine KS, Bernoud-Hubac N, Boutaud O, Montine
TJ, Roberts LJ 2nd.

Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
27232-6602, USA.

Oxidative stress can impair proteasome function, both of which are
features of neurodegenerative diseases. Inhibition of proteasome
function leads to protein accumulation and cell death. We discovered
recently the formation of highly reactive g-ketoaldehydes, isoketals
(IsoKs), and neuroketals (NeuroKs) as products of the isoprostane and
neuroprostane pathways of free radical-induced lipid peroxidation that
are analogous to cyclooxygenase-derived levuglandins (LGs). Because
aldehydes that are much less reactive than IsoKs have been shown to
inhibit proteasome function, we explored the ability of the proteasome
to degrade IsoK-adducted proteins/peptides and the effect of IsoK and
IsoK-adducted proteins/peptides on proteasome function. Adduction of
IsoK to model proteasome substrates significantly reduced their rate of
degradation by the 20S proteasome. The ability of IsoK to inhibit
proteasome function directly was observed only at very high
concentrations. However, at much lower concentrations, an IsoK-adducted
protein (ovalbumin) and peptide (Ab1-40) significantly inhibited
chymotrypsin-like activity of the 20S proteasome. Moreover, incubation
of IsoK with P19 neuroglial cultures dose-dependently inhibited
proteasome activity (IC50 = 330 nM) and induced cell death (LC50 = 670
nM). These findings suggest that IsoKs/NeuroKs/LGs can inhibit
proteasome activity and, if overproduced, may have relevance to the
pathogenesis of neurodegenerative diseases.

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