X-Message-Number: 24603
Date: Wed, 8 Sep 2004 21:04:34 -0700 (PDT)
From: Doug Skrecky <>
Subject: Could fish-every-day eliminate dementia risk?

[Below dietary DHA was found to induce a 10-fold increase in
transcription of the amyloid beta protein scavenger transthyretin.
Transthyretin might be the key to eliminating Alzheimer's.]

Neuron. 2004 Sep 2;43(5):633-45
Docosahexaenoic Acid protects from dendritic pathology in an Alzheimer's
disease mouse model.
 Learning and memory depend on dendritic spine actin assembly and
docosahexaenoic acid (DHA), an essential n-3 (omega-3) polyunsaturated
fatty acid (PFA). High DHA consumption is associated with reduced
Alzheimer's disease (AD) risk, yet mechanisms and therapeutic potential
remain elusive. Here, we report that reduction of dietary n-3 PFA in an AD
mouse model resulted in 80%-90% losses of the p85alpha subunit of
phosphatidylinositol 3-kinase and the postsynaptic actin-regulating
protein drebrin, as in AD brain. The loss of postsynaptic proteins was
associated with increased oxidation, without concomitant neuron or
presynaptic protein loss. N-3 PFA depletion increased caspase-cleaved
actin, which was localized in dendrites ultrastructurally. Treatment of
n-3 PFA-restricted mice with DHA protected against these effects and
behavioral deficits and increased antiapoptotic BAD phosphorylation. Since
n-3 PFAs are essential for p85-mediated CNS insulin signaling and
selective protection of postsynaptic proteins, these findings have
implications for neurodegenerative diseases where synaptic loss is
critical, especially AD.

Lipids. 2000 Dec;35(12):1305-12
Fatty acid analysis of blood plasma of patients with Alzheimer's disease,
other types of dementia, and cognitive impairment.
 Fatty acid differences, including docosahexaenoic acid (DHA; 22:6n-3)
have been shown in the brains of Alzheimer's patients (AD) as compared
with normal age-matched individuals. Furthermore, low serum DHA is a
significant risk factor for the development of AD. The relative
concentration of DHA and other fatty acids, however, in the plasma of AD
patients compared with patients with other kinds of dementias (other
dementias; OD), patients who are cognitively impaired but nondemented
(CIND), or normal patients is not known. In this study we analyzed the
total phospholipid, phosphatidylcholine (PC), phosphatidylethanolamine
(PE), and lysophosphatidylcholine (lysoPC) fractions of plasma from
patients diagnosed with AD, OD, or CIND and compared them with a group of
elderly control subjects with normal cognitive functioning. Plasma
phospholipid and PC levels of 20:5n-3, DHA, total n-3 fatty
acids, and the n-3/n-6 ratio were lower in the AD, OD, and CIND groups.
Plasma phospholipid 24:0 was lower in the AD, OD, and CIND groups as
compared with the group of control patients, and total n-6 fatty acid
levels were higher in the AD and CIND groups only. In the plasma PE
fraction, levels of 20:5n-3, DHA, and the total n-3 fatty acid levels were
significantly lower in the AD, OD, and CIND groups. DHA levels were lower
in the lysoPC fraction of CIND individuals only. There were no other
differences in the fatty acid compositions of the different phospholipid
fractions. Therefore, in AD, OD, and CIND individuals, low levels of n-3
fatty acids in the plasma may be a risk factor for cognitive impairment
and/or dementia. Interestingly, a decreased level of plasma DHA was not
limited to the AD patients but appears to be common in cognitive
impairment with aging.

Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1580-5. Epub 2003 Feb 03
Short-term administration of omega 3 fatty acids from fish oil results in
increased transthyretin transcription in old rat hippocampus.
 Reduced brain levels of long chain polyunsaturated fatty acids
[arachidonic acid and docosahexanoic acid (DHA)] are observed in elderly
subjects and patients with Alzheimer's disease. To determine the effects
of n-3 fatty acids on aged rat brain, 2-year-old rats were fed fish oil
(27% DHA content) for 1 month, and gene expression analysis and fatty acid
and molecular species composition of the major phospholipid species were
assessed. No significant alteration could be observed in the fatty acid
composition of ethanolamine phosphoglycerides and phosphatidylserines
with the exception of DHA, which was slightly higher in brains of rats
receiving fish oil. However, a drastic reduction in arachidonic acid in
phosphatidylinositoles was observed. The expression of 23 genes was
altered in response to fish oil feeding in the hippocampus. The
transcription of transthyretin (TTR) was induced by 10-fold as evidenced
by microarray analysis and confirmed by real-time quantitative RT-PCR.
Expression of IL-1 and NO synthase, which has been implicated in the
prevention of neurological diseases, was unaltered. TTR is an amyloid
beta protein scavenger, so an increase in its expression could
prevent amyloid aggregate formation. We believe the beneficial effects of
fish oil might be common to other agents, i.e., induce TTR expression,
like nicotine and Ginkgo biloba extract.

Arch Neurol. 2003 Jul;60(7):940-6.
Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease.
 BACKGROUND: Dietary n-3 polyunsaturated fatty acids improve brain
functioning in animal studies, but there is limited study of whether this
type of fat protects against Alzheimer disease. OBJECTIVE: To examine
whether fish consumption and intake of different types of n-3 fatty acids
protect against Alzheimer disease. DESIGN: Prospective study conducted
from 1993 through 2000, of a stratified random sample from a
geographically defined community. Participants were followed up for an
average of 3.9 years for the development of Alzheimer disease. PATIENTS:
A total of 815 residents, aged 65 to 94 years, who were initially
unaffected by Alzheimer disease and completed a dietary questionnaire on
average 2.3 years before clinical evaluation of incident disease. MAIN
OUTCOME MEASURES: Incident Alzheimer disease diagnosed in a structured
neurologic examination by means of standardized criteria.
RESULTS: A total of 131 sample participants developed Alzheimer disease.
Participants who consumed fish once per week or more had 60% less risk of
Alzheimer disease compared with those who rarely or never ate fish
(relative risk, 0.4; 95% confidence inte rval, 0.2-0.9) in a model
adjusted for age and other risk factors. Total intake of n-3
polyunsaturated fatty acids was associated with reduced risk of Alzheimer
disease, as was intake of docosahexaenoic acid (22:6n-3).
Eicosapentaenoic acid (20:5n-3) was not associated with Alzheimer
disease. The associations remained unchanged with additional
adjustment for intakes of other dietary fats and of vitamin E and for
cardiovascular conditions. CONCLUSION: Dietary intake of n-3 fatty acids
and weekly consumption of fish may reduce the risk of incident Alzheimer
disease.

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