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Medical Hypotheses (2006) 67, 682697

http://intl.elsevierhealth.com/journals/mehy

Toward prevention of alzheimers disease


Potential nutraceutical strategies for suppressing
the production of amyloid beta peptides
Mark F. McCarty
Natural Alternatives International, 1185 Linda Vista Dr., San Marcos, CA 92078, United States
Received 6 April 2006; accepted 10 April 2006

Summary Alzheimers disease (AD) can be viewed as a vicious cycle in which excess production and deposition of
amyloid beta (Ab) peptides promote microglial activation, and the resultant production of inflammatory mediators
further boosts Ab production while inducing death and dysfunction of neurons. Ab production is mediated by beta- and
gamma-secretase activities; it is prevented by alpha-secretase activity, and insulin-degrading enzyme (IDE) catabolizes
Ab. High cellular cholesterol content increases Ab synthesis by boosting beta-secretase activity; inhibition of
cholesterol syntheses and/or stimulation of cholesterol export thus diminishes Ab production. PPARc activity decreases
Ab production by promoting harmless catabolism of amyloid precursor protein while blocking the up-regulatory impact
of cytokines on beta-secretase expression. Nitric oxide produced by the healthy cerebral microvasculature can
suppress Ab production by boosting expression of alpha-secretase while suppressing that of beta-secretase; conversely,
cerebral ischemia provokes increased APP expression. Good insulin sensitivity and efficient brain insulin function
protect by inhibiting gamma-secretase activity and increasing expression of IDE. The DHA provided by fish oil
diminishes cerebral Ab deposition in rodent AD models, for unclear reasons. Various measures which oppose microglial
activation can inhibit up-regulation of beta-secretase and gamma-secretase by oxidants and cytokines, respectively.
These considerations suggest that a number of nutraceutical or lifestyle measures may have potential for preventing or
slowing AD: policosanol; 9-cis-beta-carotene; isomerized hops extract; DHA; measures which promote efficient
endothelial NO generation, such as low-salt/potassium-rich diets, exercise training, high-dose folate, and flavanol-rich
cocoa; chromium picolinate and cinnamon extract as aids for insulin sensitivity; and various agents which can oppose
microglial activation, including vitamin D, genistein, and sesamin. The impact of these measures on Ab production in
rodent models of AD should be evaluated, with the intent of defining practical strategies for AD prevention.
c 2006 Elsevier Ltd. All rights reserved.

Alzheimers disease a simple model


Although a great deal remains to be learned about
the pathogenesis of Alzheimers disease (AD), its

E-mail address: mccarty@pantox.com.

broad outlines are beginning to emerge. AD may


be viewed as a metabolic vicious cycle, characterized and driven by excessive deposition of fibrillar
aggregates of amyloid beta peptides (Ab1-40 and
Ab1-42) in afflicted regions of the brain [1,2]. The
causes of this excess deposition presumably include
one or more of the following: up-regulation of the

0306-9877/$ - see front matter c 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2006.04.067

Toward prevention of alzheimers disease Potential nutraceutical strategies


beta-secretase and gamma-secretase proteolytic
activities which generate Ab from the amyloid precursor protein (APP); down-regulation of the alphasecretase activity which precludes production of
Ab; increased synthesis or stability of APP, precursor for Ab; reduced efficiency of mechanisms which
clear or catabolize Ab, notably the insulin-degrading protease (IDE) that represents the chief extracellular proteolytic activity targeting Ab. Ab
aggregates then trigger activation of microglia,
inducing production of oxidants (most notably peroxynitrite), cytokines, and prostanoids, that work
in various ways to: (1) boost the production of Ab
by neurons and astrocytes thereby closing the vicious cycle; (2) kill neurons, either directly, or by
increasing their sensitivity to excitotoxicity; (3)
disrupt neuron structure and function by promoting
excessive phosphorylation of tau, giving rise to the
characteristic neurofibrillary tangles; (4) disrupt
the protective function of astrocytes.
A previous essay has focused on measures
including but not limited to nutraceuticals which
have potential for intervening in this vicious cycle
by decreasing the susceptibility of microglia to
activation [3]. However, effective concurrent efforts to diminish synthesis and deposition Ab would
evidently be of complementary value.

Cholesterol control
There is now very substantial evidence that a high
content of cholesterol in neural membranes increases the chances that APP will be converted
to Ab [46]. This appears to reflect the fact that
cholesterol-rich lipid raft regions of membranes
are particularly suitable for beta- and gammasecretase activities [68]. Since most cholesterol
in neurons is synthesized in situ, drugs or nutraceuticals which inhibit cholesterol synthesis potentially can impact Ab production. Indeed, the
utility of statins in this regard is well documented
in rodent models and cell cultures [4,5,9,10], and
this mechanism may account, at least in part, for
epidemiological observations noting decreased risk
for AD in subjects who used statins during mid-life
[1113].
Policosanol, a mixture of long-chain saturated
alcohols derived from sugar cane wax the chief
of which is octacosanol is reported to have clinical hypocholesterolemic activity [14,15]; this may
reflect the ability of these alcohols to down-regulate (but not wholly eliminate) expression of
HMG-CoA reductase [16,17]. Policosanol is well tolerated clinically, and unlike statins fails to kill
animals in any dose; its safety may reflect the fact

683

that it can only partially diminish HMG-CoA activity


whereas high concentrations of statins can virtually
eliminate this activity, with adverse consequences
for sensitive tissues such as skeletal muscle
[18,19]. For this reason, policosanol is particularly
suited for primary prevention. However, there does
not appear to be any published evidence that policosanol can decrease cholesterol synthesis in brain
tissues; its impact on HMG-CoA reductase expression has been demonstrated in fibroblast cell cultures, and, in vivo, it has been shown to suppress
hepatic cholesterol synthesis. Thus, it would be
of interest to determine whether policosanol
administration can influence brain cholesterol synthesis and content, and whether, like statins, policosanol can suppress production of Ab in transgenic
mouse models of AD (i.e., mice genetically altered
to express mutant forms of human APP more prone
to conversion to Ab.)
There is some reason to believe that the metabolic effects of policosanol are mediated, not by
long-chain alcohols per se, but by the corresponding long-chain fatty acids (octacosanoic acid,
etc.) derived from them by oxidative metabolism
[20]. A mixture of such long-chain fatty acids,
known as D-003 and likewise derived from sugar
cane wax, is now being developed as a hypocholesterolemic agent, and may have more potent
activity in this regard, mg per mg, than policosanol
[2123]. Thus, D-003s impact on Ab production
may also merit evaluation.
The cholesterol content of neurons is determined, not only by the rate of its in situ synthesis,
but also by the efficiency with which cholesterol is
extruded from these cells. A major catalyst in this
regard is the ATP-binding cassette protein ABCA1,
which flips cholesterol and phospholipids from the
inner membrane leaflet to the outer leaflet, where
they can be picked up by de-lipidated apolipoproteins (A1 or E) to form nascent HDL particles
[24]. The transcription of ABCA1 can be greatly enhanced by activated heterodimers of the LXRRXR
receptors [2527]. Thus, an LXR agonist has been
shown to boost expression of ABCA1 and decrease
Ab production, both in cell cultures and in transgenic AD mice giving rise to the suggestion that
LXR agonists might be useful for prevention or
treatment of AD [2831]. The chief endogenous
activators of LXR are hydroxysterols, which accumulate in cells with high cholesterol content; to
date, there are no known nutraceutical ligands
for this receptor. However, ligands for the RXR
receptor rexinoids can increase the transcriptional activity of LXRRXR heterodimers
[3235]. The chief endogenous rexinoid, 9-cis-retinoic acid (9cRA), has indeed been shown to

684
promote transcription of ABCA1, and to potentiate
the efficacy of LXR ligands in this regard
[28,32,33]. The bodys synthesis of 9cRA can be
boosted by administration of algal sources of beta
carotene (notably those derived from Dunaliella
salina) that are rich in 9-cis-beta-carotene [36],
which can be cleaved and oxidized in the intestinal
mucosa to yield 9cRA [37,38]. (Most commercial
sources of beta-carotene supply only the all-trans
isomer, which cannot be converted directly to
9cRA although the all-trans retinoic acid derived
from it can be isomerized to 9cRA to a limited extent in the liver [3941].) Supplemental betacarotene fails to evoke the toxicities associated with
retinoid excess because expression of the intestinal
enzyme which cleaves it is subject to feedback
inhibition [42]. This likely will limit the impact of
supplemental 9-cis-beta-carotene on brain cholesterol metabolism but that is the price that must
be paid for safety. While 9cRA can be administered
directly, headaches are a common clinical side effect [43].
In a recent clinical study, supplementation
with Dunaliella-derived beta-carotene was shown
to increase HDL cholesterol content in subjects
receiving concurrent fibrate therapy [44]. The
authors suggest that this impact on HDL cholesterol may have reflected up-regulation of reverse
transport mechanisms that send tissue cholesterol
to the liver via HDL. Increased activity of LXR
RXR heterodimers may well have mediated this
effect; in which case it would be reasonable to
conclude that supplementary 9-cis-beta-carotene
might have a sufficient impact on the bodys
9cRA pool to influence cholesterol transport in
the brain.
A cholesterol-enriched high-fat diet is reported
to promote increased Ab deposition in the brain of
transgenic mice [45,46]. Since most neural cholesterol is believed to be of endogenous origin, it is
not clear whether this effect reflects an increase
in brain cholesterol levels. Alternatively, high
LDL cholesterol might adversely influence the protective function of cerebrovascular endothelium
(as discussed below). In any case, if this study
has clinical relevance, it suggests that additional
measures for lowering plasma LDL cholesterol
levels could be of benefit from the standpoint of
Alzheimers risk. Indeed, elevated total cholesterol
in mid-life has been found to be a risk factor for
AD in some studies, and LDL cholesterol tends to
be elevated in AD patients [4750]; however,
not all studies support these conclusions
[5153]. Aside from policosanol, a number of
nutraceutical or dietary measures can aid control
of LDL cholesterol; these include soluble fiber,

McCarty
phytosterols, polymethoxylated flavones, tocotrienols, pantethine, and vegan diets (cholesterolfree) low in saturated fat [5469]. Tocotrienols
may share policosanols capacity to down-regulate
HMG-CoA reductase expression [62]. Whether or
not such measures would have any impact on AD
risk, keeping LDL cholesterol levels relatively low
is evidently of crucial importance for cardiovascular health.

The PPARgamma effect


PPARc ligands, as well as transfection of PPARc
DNA, have been shown to decrease Ab production
in cell cultures by two complementary mechanisms: down-regulation of the expression of APP,
owing to increased ubiquitinization and proteasomal degradation; and abrogation of the up-regulatory effect of certain cytokines (INF-gamma in
conjunction with either TNF-alpha or IL-1beta) on
beta-secretase expression [7072]. PPARc activity
may also promote Ab clearance by inducing its cellular uptake [73]. In vivo, PPARc agonists can reduce brain deposition of Ab in transgenic AD mice
[74]. Since PPARc activity also opposes the activation of microglia [7578], there is now considerable interest in testing the impact of PPARc
ligands on risk for, or progression of, AD.
Isohumulones, the chief components of isomerized hops extracts, have been shown to have agonist activity for both PPARg and PPARa in low
micromolar concentrations [79]. Moreover, dietary
administration of these compounds exerts anti-diabetic and hypolipidemic effects in rodents quite
comparable to those evoked by thiazolidinediones
and fibrates; however, unlike thiazolidinediones,
these agents tend to decrease rather than increase
fat mass in fat-fed rodents [7982]. Particularly in
light of a recent report that PPARa agonists can oppose microglial activation [83], it would be of
interest to examine the impact of isohumulones
on Ab production in cell cultures and in transgenic
mouse models of AD. In any case, it would appear
appropriate to study the utility of supplemental
hops extract for control of metabolic syndrome,
in which pharmaceutical agonists for both PPARc
and PPARa are of clinical value.
As with LXR, PPARc and PPARa each function as
heterodimers with RXR, and rexinoids boost the
transcriptional activity of these heterodimers,
whether in the presence or the absence of ligands
for the PPARs [8385]. Thus, there is reason to
hope that 9-cis-beta-carotene administration might
complement the utility of hops extract for evoking
the protective effects of PPARc and PPARa.

Toward prevention of alzheimers disease Potential nutraceutical strategies

Cerebrovascular nitric oxide


Although a healthy cerebrovasculature self-evidently minimizes risk for vascular dementia, there
is growing reason to suspect that it likewise reduces risk for AD. Thus, most risk factors for vascular disease have likewise been found to influence
AD risk, and AD patients are afflicted with more
cerebrovascular atheroma than are age-matched
controls [8690]. Of interest in this regard is the
Melanesian island of Kitava, whose residents do
not salt their food; their quasi-vegan diets (a modest intake of fish is the only animal product) are extremely rich in potassium, and the Kitavans remain
lean and insulin sensitive throughout life (albeit
cholesterol levels are not notably low, owing to
ingestion of coconut milk) [9193]. Like other nosalt societies, the Kitavans appear to be free of
hypertension, a key determinant of cerebrovascular health; moreover, a recent Swedish expedition
concluded that stroke is very rare if not absent
among these people. But the most surprising finding was that senile dementia was a foreign concept
to Kitavans they had never heard of elderly people becoming demented [94]! (This despite the fact
that a goodly proportion of Kitavans achieve a ripe
old age.) Analogously, during the early decades of
the last century, when salt was rarely used by
sub-Saharan Africans and both hypertension and
stroke were quite rare among these people, senile
dementia was reported to be extremely uncommon
[94,95]. Thus, there seems to be a correlation between excellent cerebrovascular health and freedom from both types of dementia.
How could vascular function influence the onset
of AD? Some experts speculate that chronic or
intermittent cerebral ischemia exerts a pro-inflammatory effect that up-regulates the vicious metabolic cycle that constitutes AD, or that ischemia
directly kills neurons or renders them more susceptible to other pro-apoptotic stimuli to which they
are exposed [9699]. Indeed, in rodents, intermittent or chronic hypoperfusion of the brain has often been reported to enhance expression of APP
in affected brain regions [100102]. Up-regulation
of beta-secretase, and down-regulation of alphasecretase, have also been reported following ischemic brain injury [103,104].
However, an alternative or additional possibility is that the low concentrations of nitric oxide
(NO) produced by a healthy cerebrovascular endothelium influence the function of parenchymal
brain cells in a protective way [105,106]. Until recently, there was little but speculation to support
that latter possibility. However, a new study re-

685

veals that, in cultured human neuroblastoma


cells, low concentrations of NO up-regulate the
expression of alpha-secretase, while down-regulating that of beta-secretase suggesting that,
in the relative absence of superoxide, cerebrovascular NO might act to suppress brain production of
Ab [107]. Further studies should examine more directly the impact of NO on APP metabolism in
cells cultures, and, using drugs that specifically inhibit the endothelial isoform of NO synthase,
should assess the impact of cerebrovascular NO
on Ab production in transgenic mice. Such studies
could clarify whether cerebrovascular NO does indeed exert a protective anti-inflammatory effect
on the brain.
Promoting cerebrovascular health is in any case
a high priority, as stroke and vascular dementia
are major public health problems. Nutritional and
lifestyle measures likely to be of use in this regard
include a low-salt, potassium-rich diet; aerobic
exercise training; thermal therapy (i.e., saunas,
hot baths); fish oil; high-dose folate; agents which
promote good insulin sensitivity (such as chromium
picolinate or cinnamon extracts); policosanol
(which may mimic the protective effects of statins); and probably flavanol-rich cocoa powder
[94,108119]. Pharmacological or nutraceutical
control of hypertension is clearly a high priority
for promotion of cerebrovascular health.
In regard to endothelial NO synthase activity in
particular, it should be noted that shear stress (as
evoked by aerobic exercise), thermal therapy,
DHA (from fish oil), and statins all have been shown
to increase expression of this enzyme in vascular
endothelium [108111,116,117]. In the context of
vascular oxidant stress, high-dose folate increases
the activity of eNOS by somehow compensating
for the oxidative loss of tetrahydrobiopterin, while
preventing this enzyme from generating superoxide
[112114]. Statins, independent of their impact on
plasma cholesterol, can act directly on vascular
endothelium to up-regulate expression of eNOS
while suppressing endothelial oxidant production
[116,117,120]; the possibility that policosanol (or
D-003) have comparable utility merits evaluation.
Finally, the flavanols in unprocessed cocoa powder
(most notably epicatechin) act directly on endothelium to stimulate eNO synthase activity
[118,119]; thus, cocoa ingestion has been found
to boost cerebral blood flow. Intriguingly, the Kuna
Indians, native to islands off the coast of Panama,
drink several servings of unprocessed cocoa a day,
and appear to be the only known society which
salts its food and yet is free from hypertension
[121].

686
The Kitavan experience points to dietary salt
(and possibly potassium) as a major determinant
of cerebrovascular health. In the context of salt
sensitivity, salt consumption may compromise NO
function by boosting endothelial superoxide production; conversely, high potassium intakes have
an anti-oxidant impact on endothelium [122
127]. Could stroke and even senile dementia be
viewed as a disease of civilization made possible
by salted diets, just as coronary disease can be
viewed as a disease of civilization made possible
by rich refined diets that boost LDL cholesterol?
As a proviso, it should be noted that, whereas lifelong consumption of unsalted diets seems to do a
marvelous job of preventing hypertension and possibly stroke, initiation of such diets later in life usually fails to normalize elevated blood pressure, and
often does not lower blood pressure at all; this
salt paradox still awaits an explanation.
Although supplemental arginine can increase
eNOS activity when plasma ADMA levels are elevated, it can also increase NO production by iNOS,
a major factor in microglial activation [128,129];
moreover, arginine positively regulates the expression of iNOS [130]. Thus, arginine supplementation
is a two-edged sword as suggested by a recent
clinical trial in cardiac patients [131] and probably would not be appropriate for patients in whom
the microglial activation is already in progress.
Once the inflammatory process of AD is well
underway, superoxide production by activated
microglia as well as by vascular endothelium itself
(induced by Ab) [132134] could be expected to
antagonize any direct protective effects of vascular NO on brain function. Thus, boosting cerebrovascular NO production likely would be of more
benefit for prevention than for therapy.

Impact of insulin sensitivity and cerebral


insulin
Insulin resistance syndrome has emerged as a notable risk factor for AD in the absence of apoE4 [135
139]. Although efficient systemic insulin activity is
beneficial for cerebrovascular health, and is associated epidemiologically with reduced stroke risk
[140,141], there is reason to suspect that efficient
insulin function within the brain parenchyma itself
may decrease Ab deposition. Although insulin
activity is not required for glucose transport in
most neurons, the insulin receptor is expressed by
neurons in many regions of the brain, including
those characteristically afflicted by AD pathology,
and influences their function via tyrosine kinase

McCarty
activity; moreover, systemic insulin is transported
to the brain through the bloodbrain barrier via a
saturable carrier mechanism that is still poorly
characterized [142].
In cell culture studies, efficient insulin activity
has been found to decrease Ab levels by at least
two mechanisms. Firstly, insulin boosts expression
of insulin-degrading enzyme (IDE), the chief extracellular protease which targets and catabolizes Ab
[143146]. Secondly, insulin deactivates (via the
PI3K-Akt pathway) glycogen synthase kinase-3a;
the latter, which is constitutively active when not
inhibited by phosphorylation, up-regulates the
activity of gamma-secretase, and thereby promotes Ab production [147].
On the other hand, high levels of insulin within
the brain may have the potential to abrogate the
impact of IDE on Ab by acting as a competitive substrate for this enzyme [145]. And a recent clinical
study found that, in healthy subjects subjected to
insulin infusion under euglycemic conditions,
induced hyperinsulinemia was attended by a rapid
increase in plasma and CSF levels of Ab1-42 and
of various cytokines [148]. Moreover, the elevated
risk for AD in type 2 diabetics is greatest in those
treated with drugs that boost plasma insulin sulfonylureas or injectible insulin [144,149,150].
Thus, there is some reason to suspect that hyperinsulinemia per se may increase AD risk despite the
favorable impact of insulin activity on Ab production and half-life in vitro.
Systemic hyperinsulinemia may not always
translate into high brain levels of insulin; some
though not all studies report that, in the context
of obesity/insulin resistance syndrome, the efficiency of bloodbrain barrier insulin transport is
impaired, such that brain insulin levels may be normal despite elevated plasma insulin [151,152].
Also, it is not yet clear whether the typical metabolic syndrome entails a reduction in cerebral
responsiveness to insulin. In this regard, a recent
study found that, when transgenic AD mice were
fed a high-fat diet that induced obesity and insulin
resistance, hippocampal levels of both isoforms of
Ab increased; this phenomenon was associated
with increased gamma-secretase activity, reduced
expression of IDE, reduced activation of the PI3KAkt pathway, and decreased phosphorylation of
glycogen synthase kinase-3a effects consistent
with decreased cerebral insulin activity in the face
of systemic hyperinsulinemia [153]. It is not clear
whether this reduced activity reflected decreased
cerebral insulin levels, decreased cerebral insulin
responsiveness, or perhaps both.
In any case, it seems reasonable to speculate
that good systemic insulin sensitivity, associated

Toward prevention of alzheimers disease Potential nutraceutical strategies


with moderate plasma and brain insulin levels, is
likely to be associated with adequate cerebral insulin activity that is protective with respect to AD
risk. It would be of interest to test the impact of
various insulin-sensitizing nutraceuticals (i.e.,
chromium picolinate, cinnamon extract) on transgenic AD mice fed high-fat diets [154162].
With respect to cinnamon, its favorable impact
on insulin sensitivity is thought to reflect inhibition
of PTP-1B by hydroxychalcone compounds [163].
The phosphatase activity of PTP-1B targets the
insulin receptor [164,165], and thus down-regulates the PI3K-Akt pathway that suppresses neural
generation of Ab. In addition, PTP-1B functions in
hepatocytes to boost the transcriptional activity
of Sp1 by relieving an inhibitory phosphorylation
[166]. Analysis of the beta-secretase promoter
revealed the presence of an Sp1 response element,
and Sp1 has in fact been shown to boost
beta-secretase transcription [167]. Thus, it is conceivable that cinnamon extract could suppress
beta-secretase transcription by inhibiting Sp1
function via its impact on PTP-1B. However, it is
currently unknown whether the active factors in
cinnamon can cross the bloodbrain barrier.

Fish oil
A high dietary intake of fish has been linked to decreased AD risk in epidemiological studies [168
170]. Presumably, a portion of this putative effect
may be attributable to the favorable effects of fish
oil on cerebrovascular function the impact of
DHA on eNOS expression has been noted, and risk
for ischemic stroke appears to be lower in those
with a regular intake of fatty fish [171176]. A diet
enriched in DHA has recently been shown to decrease cortical levels of insoluble Ab quite markedly in transgenic AD mice; a trend toward
reduction in soluble Ab did not achieve statistical
significance [177]. The reason for this substantial
decrease in insoluble Ab remains obscure; further
studies should be conducted to clarify the impact
of DHA on APP metabolism.

Down-regulating microglial function


Activated microglia are observed in AD plaque, and
the increased levels of nitrotyrosine found in these
plaques suggest that these microglia produce ample quantities of peroxynitrite [178184]. Fibrillar
Ab aggregates can activate microglia [185,186];

687

in vitro, this effect is contingent on concurrent


stimulation with INF-gamma, but, in vivo, infusion
of Ab alone is sufficient to trigger such activation
suggesting that ambient cerebral levels of INF-gamma or of some compound with analogous activity
tend to be high enough to support Ab-mediated
microglial activation [187,188].
The oxidants, cytokines, and prostanoids produced by activated microglia appear to have a dual
impact on neurons: they boost production of Ab,
and they induce apoptosis. Peroxynitrite appears
to be the chief mediator of neuron death [189].
When microglia and neurons are co-cultured in
the presence of LPS or Ab plus INF-gamma (thus
promoting microglial activation), neurons in the
immediate vicinity of microglia are killed; this effect is substantially alleviated if peroxynitrite scavengers are added [190]. Peroxynitrite also
increases neural sensitivity to excitotoxicity
[191], and potentiates the direct toxicity of Ab to
neurons [192]. However, other studies, in which
neurons are exposed to conditioned media from
activated microglia, suggest that microglial cytokines can also contribute to neural death (albeit
neuronal production of peroxynitrite reflecting
iNOS induction in neurons mediates this process)
[193].
In regard to APP metabolism, either IL-1 or TNFalpha, in conjunction with INF-gamma, have been
found to increase Ab production by boosting
expression of APP while enhancing gamma-secretase activity [194,195]. The chief COX product
PGE2 likewise promotes Ab generation by stimulating gamma-secretase activity [196]. The up-regulatory impact of oxidant stress on Ab production has
been traced to a stress-activated kinase-mediated
increase in beta-secretase transcription [197
201]; activation of these kinases also promotes
the hyperphosphorylation of tau that induces neurofibrillar tangles [202]. The fact that iNOS knockout markedly reduces Ab deposition in the brains
of transgenic AD mice, suggests that peroxynitrite
does indeed have an important impact on APP processing in vivo [203].
Cox-2 overexpression boosts Ab production in
transgenic AD mice, an effect likely mediated by
PGE2 [204]. However, some (most notably ibuprofen) but not all NSAIDS inhibit Ab production in cell
cultures; this effect seems to be independent of
cox-inhibition, and instead appears to reflect a direct inhibitory effect on gamma-secretase activity
[205,206]. Perhaps this explains why regular NSAID
use emerges as protective in epidemiology [207],
whereas clinical efforts to treat AD with cox-2-specific NSAIDs have not proved fruitful [208]. The suggestion that ibuprofens impact on Ab metabolism

688
reflects PPARgamma agonist activity [74] probably
has little clinical relevance, as clinical doses of ibuprofen do not have thiazolidinedione-like activity
in diabetics.
Activated microglia may also adversely influence
the function and survival of neurons less directly
by impairing astrocyte function. Healthy astrocytes
protect neurons by sequestering glutamate thus
alleviating excitotoxicity. Peroxynitrite, cox-2
products, and microglial-derived cytokines have
all been shown to impair glutamate uptake by
astrocytes [209215]. Thus, it is reasonable to suspect that excitotoxity contributes to neuronal
death and dysfunction in AD as indeed is borne
about by the utility of the NMDA receptor antagonist memantine in the treatment of this disorder
[216,217]. Furthermore, peroxynitrite and PGE2
can increase the susceptibility of neurons to excitotoxic cell death [191,213,218].
These considerations strongly suggest that measures which can safely down-regulate microglial
activation should be useful for the prevention or
treatment of AD. As cited in a recent review [3], such
measures may include: the antibiotic minocycline,
PPARgamma agonists, genistein, vitamin D, cox-2
inhibitors, statins, cannabinoids, and sesamin. A recent report provides evidence that PPARalpha agonists can also suppress microglial activation [83].
Several of these strategies may be achievable with
nutraceuticals. As noted above, hops extract has
agonist activity for both PPARalpha and PPARgamma, and its efficacy in this regard might be potentiated by co-administration of 9-cis-beta-carotene.
Genistein, the soy isoflavone, is an agonist for the
beta isoform of the estrogen receptor in physiologically achievable concentrations [219], and it can be
expected to down-regulate microglial function
through activation of this receptor [220]. Conceivably, genisteins protective activity in murine models of ALS and stroke [221] reflects its impact on
microglia. Microglial activation induces expression
of the 1alpha-hydroxylase that converts 25-hydroxyvitamin D to its active hormonal form calcitriol
[222]; via vitamin D receptor activity, calcitriol suppresses induction of iNOS, while boosting astrocyte
expression of protective neural growth factors
[223227]. 9-cis-Beta-carotene may have the potential to boost calcitriol activity, as the vitamin D
receptor functions as a heterodimer with RXR
[228]. The possibility that policosanol (or D-003)
might mimic the protective benefits of statins has
been noted. Sesamin, a lignan from sesame seeds,
inhibits LPS-mediated activation of microglia
in vitro, and, provides protection from rotenoneinduced Parkinsonism (an effect likely reflective of
decreased microglial activation) [229231].

McCarty

Ancillary neuroprotective measures


Nutrients or drugs which boost the anti-oxidant defenses of neurons, support their bioenergetic efficiency, or that decrease neural release of
glutamate (thereby alleviating excitotoxicity) have
shown utility in various animal models of neurodegenerative diseases, and some of these might have
potential for slowing the progression of Alzheimers. High caffeine intakes have been linked to reduced risk for Parkinsons disease, but there is also
some epidemiological evidence that coffee drinkers are at lower risk for Alzheimers [232,233]. This
possibly reflects the fact that caffeine is an antagonist for adenosine receptors (A2A) expressed presynaptically by excitatory neurons; caffeine blocks
the ability of adenosine to provoke glutamate release from these terminals [234237]. Cannabinoids exert an analogous effect [238240]; in
addition, they inhibit LPS-mediated induction of
iNOS in microglia, an effect which is thought to explain their favorable impact on the toxicity of
intracerebrally administered Ab in mice [241
243]. There does not appear to be any epidemiology evaluating incidence of AD in regular cannabis
users.
ince products of lipid peroxidation mediate
some of the adverse effects of peroxynitrite on
neurons [200], it would be reasonable to expect
that vitamin E might have a favorable effect on
AD progression. Indeed, this was the conclusion of
a large placebo-controlled trial which evaluated
2000 IU daily in patients with mild AD [244]. Gamma-tocopherol might be worthy of evaluation as
well, since, unlike alpha-tocopherol, it can act as
a scavenger for peroxynitrite [245,246]; indeed,
there is evidence that it serves this function in AD
[184]. Lipoic acid, a phase II inducer, can increase
glutathione expression in neurons, and has demonstrated neuroprotective activity in diabetes, cerebral ischemia-reperfusion injury, and in a rodent
model of ALS [247253]; it has not yet been evaluated in transgenic AD mice or in human AD
although, in vitro, it can protect cortical neurons
from amyloid-induced cell death [254]. Creatine
and coenzyme Q10 are cofactors for bioenergetics
that have been found to slow progression of Parkinsons disease, and that also show efficacy in certain
rodent models of neurodegeneration [255262];
whether they might influence the disease process
in AD remains unclear. The potential utility of bioenergy catalysts in neurodegenerative conditions
may reflect the fact that mitochondrial damage
contributes importantly to the pathological impact
of oxidant stress on neurons [262,263].

Toward prevention of alzheimers disease Potential nutraceutical strategies


A portion of the protection from AD associated
with ample dietary intakes of fish oil may reflect
neuroprotection mediated by DHA. Thus, DHA protects neurons from Ab-induced apoptosis in vitro,
and, when fed to mice receiving intracerebroventricular infusions of Ab, ameliorated the induced
decline in learning ability [264,265]. There is recent evidence that DHA is the biosynthetic precursor for a compound, neuroprotectin-1, that
protects neurons from apoptosis [266].

Summing up
The above discussion suggests that production and
retention of Ab might be controlled by nutraceutical measures that decrease neuron cholesterol synthesis (policosanol or D-003), promote cholesterol
export (9-cis-beta-carotene as a source of 9cRA),
or that boost PPARgamma activity (isohumulones
from hops extract, 9-cis-beta-carotene). Since low
concentrations of NO appear to have a favorable
impact on APP processing, and since good cerebral
perfusion may favorably influence AD risk in other
ways, a range of nutraceutical, dietary, and lifestyle measures which promote efficient NO production by the cerebral vasculature seem likely to be
protective; these include a low-salt/high-potassium diet, aerobic exercise training, fish oil (DHA),
high-dose folate, flavanol-rich cocoa powder, and
possibly policosanol. Good insulin sensitivity also
has a favorable impact on cerebrovascular health,
and efficient insulin activity in the brain itself may
decrease expression of beta-secretase while promoting IDE-mediated Ab catabolism; conversely,
insulin resistance syndrome has emerged as an
important risk factor for AD. Whether insulin-sensitizing nutraceuticals such as chromium picolinate
and cinnamon extract can reduce cerebral Ab deposition in the context of insulin resistance syndrome,
merits evaluation. High fish consumption has been
linked to reduced AD risk in epidemiology, and
DHA limits Ab deposition in transgenic AD mice for
reasons that are not yet clear.
The process of AD appears to consist of a vicious
cycle in which increased production of Ab leads to
excessive activation of microglia, which in turn release agents that further boost production of Ab
while also inducing or up-regulating neural apoptosis. Thus, measures which suppress microglial activation would be expected to prevent an
acceleration of Ab production, while helping to
preserve the viability of neurons. Nutraceuticals
that might be helpful in this regard include vitamin
D, genistein, hops extract, 9-cis-beta-carotene,
policosanol, and sesamin.

689

Finally, certain nutraceutical have general neuroprotective activity, either because they boost
anti-oxidant defenses, aid bioenergetics, or reduce
glutamate release from excitatory terminals; these
measures might or might not influence Ab production, but they have the potential to retard neuron
loss and thus slow progression of the clinical syndrome. Vitamin E, lipoic acid, creatine, coenzyme
Q10, and caffeine are of particular interest in this
regard, and have shown neuroprotective activity
in animal models of various neurodegenerative disorders; with the exception of vitamin E, however,
little evidence is currently available regarding their
impact on animal models of AD or on the clinical
syndrome though some epidemiology suggests
that high caffeine intakes may decrease risk for AD.
This essay has focused on nutraceutical measures, because it is presumed that such measures
would be safest, most convenient, and most
affordable for use in primary prevention. Further
research with these agents in rodent models of
AD, and, ultimately, in clinical trials, may help us
to discern which of the numerous measures cited
above are most likely to provide meaningful protective benefit. Ultimately, it should prove feasible
to develop complex nutraceutical regimens which
can provide protection from AD and other neurodegenerative disorders, while also favorably influencing vascular health, insulin sensitivity, and perhaps
other health parameters. It stands to reason that
addressing the AD process at numerous complementary points, rather than attempting to control
it with one or two wonder drugs, would be more
likely to achieve success; it is inherently easier to
effect such a strategy with nutraceuticals than
with prescription drugs. Nonetheless, there clearly
will be a role for drug therapy perhaps as a complement to safe nutraceutical measures in patients who are starting to lose intellectual
function, or who are known to be at high genetic
risk for early-onset AD.

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