( 16-01-11) Omega-3 Fatty Acids Modulate Initiation and Progression of Neurodegenerative Disease

Dietary long-chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFAs), such as
docosahexaenoic acid (DHA), are essential for the normal structure and function
of the brain and the homeostatic or stabilizing functions of the central
nervous system. The life-long bioavailability of DHA benefits the health and
activity of visual, neurovascular, cardiovascular and neurological tissues.

DHA is primarily synthesized in microalgae that are food sources for marine
animals. DHA can reach concentrations up to 11% of oil from fatty fish, such as
salmon. The n-3 fatty acid alpha linolenic acid, which is enriched in some
plants, such as soybean, flax and walnuts, can be taken up by the liver,
elongated and desaturated to DHA, and transported through the blood stream to
brain and retinal targets. Although alpha linolenic acid is present in the
diet, humans have very limited ability to convert this fatty acid to the longer
chain DHA. Notably, this ability to metabolize alpha linolenic acid to DHA is
lacking in human neurons, although a 1% rate of conversion was reported in
short-term studies of rat brain. Others have reported a low rate of conversion
in cultured rat hippocampal neurons. In neonatal baboons, the conversion rate
in was about 0.6%.

During fetal and postnatal development, human infants rapidly accumulate DHA
in the brain and retina. Through highly regulated enzyme-mediated activities,
DHA bound to neural and retinal membranes is released as an oxygenated form
that functions in potent neuroprotective, anti-inflammatory, and signaling
roles in the brain and retina. This novel DHA docosanoid derivative, 10,17S-
docosatriene, was called by the investigators neuroprotectin D1 (NPD1). Unbound
DHA increases during brain injury, cerebral ischemia (stroke), epileptic
seizures and other neuropathological conditions. Changes in oxidative stress?a
pathologic condition in response to cytotoxic oxidants and free radicals that
leads to cell damage?are influenced by the availability of antioxidants, which
may further affect DHA and NPD1 actions. For example, co-supplementation of DHA
with antioxidants, such as the carotenoid lutein, significantly improved mental
processes in clinical studies of the aged. Other factors, such as the
neurotrophic pigment epithelium-derived factor and the brain-derived
neurotrophic factor, also participate in modifying oxidative stress by
stimulating the synthesis of NPD1.

Neuroprotection of photoreceptor and retinal pigment epithelial cells

The Bazan research group recently highlighted the specificity and potency of
NPD1 for neuroprotection of the photoreceptors in the retina during their
renewal. The process involves the retinal pigment epithelial cell DHA and NPD1
whose interactions protect against oxidative stress and promote the survival of
the photoreceptor and retinal pigment epithelial cells. It has been suggested
that disruption of NPD1 in the renewal of photoreceptor cells may contribute to
retinal degenerative diseases, such as age-related macular degeneration. Recent
findings showed an association between consuming a diet rich in DHA and a lower
progression of age-related macular degeneration. Bazan?s group has also
reported that NPD1 modulates pro-inflammatory signaling and promotes retinal
pigment epithelial cell survival during oxidative stress, thereby protecting
these cells from destruction.

Neuroprotection during brain oxygen deprivation and restoration (ischemia?
reperfusion)

When blood flow to a tissue is sharply reduced, as in a major heart attack or
stroke, local areas of tissue are deprived of oxygen (ischemia), and cells are
damaged and may die. Restoration of the blood supply furnishes nutrients and
halts the loss of cells. However, during ischemia, various cell-protective
mechanisms are invoked, including anti-apoptotic signaling via NPD1 production.
This response results in the increased production of anti-apoptotic proteins
and the inhibition of pro-apoptotic proteins, such as the respective members of
the Bcl-2 family. DHA perfusion was also reported to reduce the size of the
infarct volume and to improve the neurologic score compared with vehicle-
infused animals. DHA and NPD1 also contribute to the suppression of
inflammatory signaling mediated by cytokines.

The beneficial health effects of dietary fish oils on cardiovascular and brain
functions are known. Substitution of PUFA for dietary saturated fatty acids can
result in lowered heart rate, relaxation of smooth cardiac muscle, decreased
blood pressure, increased ventricular ejection and reduced risk of cardiac
arrhythmias, all with important neurological implications. DHA has potential
benefits in modulating the pathogenic events associated with brain and retinal
ischemia-reperfusion. In brain ischemia-reperfusion, DHA is released and used
for NPD1 synthesis, which in turn elicits neuroprotection. The availability of
the anti-apoptotic members of the BCL-2 family of proteins is positively
modulated by NPD1, whereas pro-apoptotic BCL-2 proteins are negatively
regulated, as is the arrival of leukocytes due to neurovascular unit breakdown.
Ischemia is one of the most common causes of heart attacks and stroke. Since
the original reports of DHA's potential neuroprotective effects, treatment
protocols have been optimized to maximize the efficacy.

DHA and NPD1 in Alzheimer's Disease

Alzheimer?s disease (AD) is a progressive neurologic disease of the brain that
leads to the irreversible loss of neurons and dementia. In AD, brain tissue
gradually shrinks (Figure). In its early stages, short-term memory begins to
fade and the ability to perform routine tasks declines as the cells in the
hippocampus degenerate. As the condition progresses through the cerebral
cortex, judgment declines, emotional outbursts may occur and language is
impaired. As Palacios-Pelaez and colleagues describe, AD typically develops
progressively with aging; acts in chronic, cooperative and integrative ways;
specifically affects the neurons of the hippocampus and neocortex (top layer of
the cerebral cortex); and exhibits positive feedback that continues until all
brain cell defenses are used up. The eventual result is irreversible
degeneration and death of neurons.

Both the amount of DHA and NPD1 and their neuroprotective functions are
reduced in hippocampal and neocortical areas of AD patient brains when compared
with those of age-matched controls. It is noteworthy that these changes are not
observed in brain areas where there is no AD-specific neuropathology. The
affected brain tissue also exhibits excessive oxidative stress markers that are
positively correlated with AD severity. Among the earliest events in AD are
impaired mitochondrial function, which results in oxidative damage,
peroxidation of membrane lipids and PUFAs by very active oxygen molecules
called reactive oxygen species, and enhanced pro-inflammatory gene expression.
Because of its high degree of unsaturation, DHA is a likely primary lipid
peroxidation target during oxidative brain cell injury and in AD, as suggested
by the elevation of the DHA peroxidation product F4 isoprostane in brain cortex
regions in AD.

A pathogenic role for DHA oxidation in AD is also supported by
epidemiological, autopsy and cerebrospinal fluid data. An early study showed
significantly lower levels of phosphatidylethanolamine-derived DHA in the human
AD brain and another study reported it was substantially decreased in in the
frontal gray matter, frontal white matter, hippocampus and pons in the AD
patient brain. There is now good evidence that oxidative stress and fatty
oxidation are likely involved in the progress of AD.

Although DHA oxidation may be involved in AD pathogenesis, DHA is also
neuroprotective against AD via multiple mechanisms. Mechanistically, these can
be explained by the anti-inflammatory action of DHA. The Bazan research group
explored the effects of DHA and NPD1 on the expression of a host of genes with
pro- or anti-inflammatory and apoptotic effects in neural cells in relation to
AD. They first found that NPD1 is drastically reduced in specific areas of the
hippocampus in AD patients.

Another characteristic pathology of AD is the accumulation of abnormal beta-
amyloid proteins. These promote the inflammatory responses and neurotoxic
pathways that lead to brain cell dysfunction. The Bazan group showed in
cultured human brain cells that when NPD1 decreases, the processing of the
amyloid-beta precursor protein, switches off pro-inflammatory gene expression
and promotes neural cell survival. The chain of events that lead to apoptosis
involves multiple checkpoints. NPD1 regulation targets several cellular events
that lead to apoptosis, thereby promoting cell stability and survival. Further
exploration is needed to resolve the dichotomy between DHA being not only a
target of lipid peroxidation resulting in progression of AD, but also a
precursor to a neuroprotective signaling.

In summary, the Bazan research group has studied several mechanisms by which
DHA and its docosanoid derivative NPD1 contribute positively to brain and
retinal health. These mechanisms include: (i) enhancement of membrane
functional integrity, (ii) recruitment and up-regulation of anti-apoptotic
genes, (iii) repression of proteins that regulate apoptosis, (iv)
downregulation of inflammatory mediators such as the enzyme cyclooxygenase-2,
and (v) modulation of kinase-mediated (Bl-2 gene family) phosphorylation.
Additional research to determine how the specific cellular and signaling
components of the cells in the neurovascular complex contribute to these
mechanisms is underway.

Source: Palacios-Pelaez R, Lukiw WJ, Bazan NG. Omega-3 essential fatty acids modulate
initiation and progression of neurodegenerative disease. Mol Neurobiol 2010;41:
367?374. [PubMed]

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