Nutritional Deficiencies in Alzheimer’s Disease
The prevalence of AD
doubles
for every decade beyond 65…
What is the most difficult
hurdle faced
in developing a treatment for AD?
The cytoskeleton consists
of
polymers & “associated” proteins
that cross-link the polymers
Binding of associated proteins to microtubules is regulated by phosphorylation
Phosphorylation of tau and
its potential role
in degeneration of neurons
PHFs cannot be transported into axons and instead clog the cell body
Another “player”
in AD…
ß-amyloid
(“ßA”)
bA is neurotoxic to neurons in culture
bA induces tau phosphorylation
bA treatment induces apoptosis
Are we simply living too long?
Current studies suggest that Alzheimer’s disease may be a disorder of Oxidative Stress
Why are neurons uniquely
susceptible to
metabolic problems such as oxidative stress?
MAP kinase regulates all
major effects
of b-amyloid on cultured neurons
MAP kinase mediates
Abeta-induced
apoptosis
MAP kinase induces sustained channel activity...
How can we block this cascade?
Three major religions that worship neurodegeneration in AD...
Phospho-tau is
induced in
cortical neurons
by ßA
Reactive oxygen species are prominent in degenerating neurons following ßA exposure
Preventing ROS accumulation by treatment with vitamin E promotes survival in culture
Reduced Folate Levels in Neurodegenerative Disorders
How do folate levels modulate neuronal health?
Folate deficiency induces accumulation of phospho-tau
“Long-term” folate deprivation induces apoptosis
Efficacy of vitamin E & folate against ROS in mouse brain
Folate regulates Abeta-induced ROS generation
Folate deficiency increases homocysteine (HC)
HC potentiates Abeta-induced cytosolic calcium accumulation
HC potentiates Abeta-induced apoptosis: Role of oxidative stress
HC sequentially activates calcium channels
A familial AD linkage for HC...
More on
the
pathological consequences
of folate deprivation later,
in relation to drug treatments...
Beneficial Effects
of
Acetyl-L-Carnitine in AD
ALCAR prevents apoptosis following Abeta exposure
Abeta depletes neuronal energy; ALCAR restores energy & minimizes neurodegeneration
“Nutrition-based”
Combinatorial approach...
Efficacy of our “nutrition-based” combinatorial approach
Methionine Cycle and Neurodegeneration
Pertubations of the
Methionine Cycle:
Consequences of Folate/B12 Deficiency
Compensation for Folate/B12
Deficiency:
Treatment with 3-DZA
DZA attenutates ROS generation following folate deprivation
Compensation for Folate/B12
Deficiency:
Treatment with NAC
N-acetyl-L-cysteine inhibits ROS formation in neurons
Delayed application of NAC is effective, while that of vitamin E is not
Compensation for Folate/B12
Deficiency:
Treatment with SAM
Watch this space
for exciting results
on the effects of SAM!!
“Drug-based”
Combinatorial approach...
Combined treatment with DZA, SAM & NAC