2012-05-01

link between alz and sugar may be cholesterol

4.13: news.health/alz/
 link between alz and sugar may be cholesterol:
4.13, 4.17: summary:
. when alzheimers was reported to be a clumping of protein
and related to diabetes,
I had assumed it was a glycation problem,
but here is evidence that cholesterol is implicated
by way of reducing leptin levels
which apparently is what prevents the formation of amyloid-β
and the occurrence of phosphorylated tau .
. the way it all ties together is that
cholesterol is elevated by sugary diet,
and a sugary diet is a leading cause of diabetes
(see the theory and results of an epi'study).


. also noticed today: a 2010 study showing
Caffeine Protects Against Disruptions of the Blood-Brain Barrier
and they were saying
that might be the way that it is protective against
both alzheimers and parkinson's disease,
-- 2 very common neurological disorders .

. toward an alternative theory,
I thought it notable that caffeine can
reduce the risk of type-2 diabetes
even when it increases insulin resistance,
because it affects basal energy expenditure,
fat oxidation stimulation,
glycogen mobilization in muscles,
and stimulation of increased lipolysis from peripheral tissues.
. caffeine is an anti-diabetic
(increases insulin sensitivity or glucose utilization).

. the potent cholesterol raiser in coffee is Cafestol;
but, some coffees -- even when decaffeinated --
will increase the brain's glucose utilization
which prevents both diabetes and alzheimers .

. misfolding of human islet amyloid polypeptide (hIAPP)
may contribute to insulin-resistance
and several factors in coffee may inhibit this .

. islet amyloid polypeptide (IAPP) also known as Amylin,
it is cosecreted with insulin from the pancreatic β-cells
in a ratio of approximately 100:1.
Amylin plays a role in glycemic regulation by
slowing gastric emptying and promoting satiety,
thereby preventing post-prandial
spikes in blood glucose levels.
. amylin, like the related beta-amyloid (Abeta)
associated with Alzheimer's disease,
can induce apoptotic cell-death in
insulin-producing beta cells,
an effect that may be relevant to
the development of type 2 diabetes .
. human amylin shares common toxicity targets with
beta-amyloid (Abeta),
providing evidence that type 2 diabetes
and Alzheimer's disease
share common toxicity mechanisms.
. pro-IAPP is secreted along with any pro-insulin;
and, when the demand for insulin is high,
then the enzymes that convert these precursor molecules
into insulin and IAPP, respectively,
are not able to keep up with the high levels of secretion,
ultimately leading to the accumulation of pro-IAPP.
It is thought that proIAPP forms the first granules
that allow for IAPP to aggregate and form amyloid .
. during IAPP's  amyloid fibrillization reaction,
the early prefibrillar structures are extremely toxic
to beta-cell and insuloma cell cultures.
Studies have shown that fibrils are the end product
and not necessarily the most toxic
form of amyloid proteins/peptides .
Initially, the proIAPP aggregates inside the cell.
The proIAPP acts as a seed,
collecting IAPP from neighboring cells
and forming an intracellular amyloid.
The amyloid formation might be
a major mediator of islet β-cell apoptosis,
As the amyloid grows, it spreads outside of the cell.
The extracellular amyloid begins to excrete IAPP to other cells,
inducing an apoptosis cascade .
. Type 2 diabetes [from overuse of sugar and grains]
is overexpressing pro-IAPP which then results in
the loss of islet β-cells. ]
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lef.org's report:
. March 9, 2012 Journal of Alzheimer's Disease
describes research conducted by Othman Ghribi, PHD ...
In previous research, Dr Ghribi's team demonstrated that
the intake of a high cholesterol diet
results in Alzheimer's disease-like changes
and iron deposition in the brains of experimental animals.
In the current study,
rabbits were given a high cholesterol diet for 12 weeks,
which resulted in the formation of brain plaques
containing the protein amyloid beta,
which is a characteristic of Alzheimer's disease.
The animals also underwent increased phosphorylation
of a protein in the brain's neurons known as tau,
which is another hallmark of the disease.
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abstracts including Othman Ghribi
2008.12: Potential Mechanisms Linking Cholesterol to
Alzheimer's Disease-like Pathology in Rabbit Brain,
Hippocampal Organotypic Slices, and Skeletal Muscle:

. Epidemiological, animal, and cellular studies suggest that
abnormalities in cholesterol metabolism are important in
the pathogenesis of Alzheimer's disease (AD),
potentially by increasing amyloid-β (Aβ) peptide levels.
Accumulation of Aβ in the brain
is suggested to play a key role by
triggering the hyperphosphorylation of tau
and the neuronal death that develop in the course of AD.
. what are the mechanisms by which
cholesterol increases Aβ levels ?
. hypercholesterolemia leads to
increased neuronal cholesterol
and increased levels and processing of the
amyloid-β protein precursor (AβPP).
the oxidized cholesterol metabolite,
27-hydroxycholesterol,
increases Aβ levels in both organotypic hippocampal slices
and in neuronal preparations cultured from adult rabbits.
This cholesterol metabolite is predominantly formed in the circulation
and, in contrast to cholesterol, has the ability to cross into the brain.
These results may indicate that 27-hydroxycholesterol
is the link between circulating cholesterol
and AD-like pathology in the brain.
2010.02: Caffeine Protects Against
Disruptions of the Blood-Brain Barrier
in Animal Models of Alzheimer's and Parkinson's Diseases
(Xuesong Chen, Othman Ghribi, Jonathan D. Geiger):

Sporadic Alzheimer's disease (AD) and Parkinson's disease (PD)
are two of the most common neurodegenerative diseases .
. caffeine has been shown in human and animal studies
to be protective against AD and PD.
One mechanism implicated in the pathogenesis of AD and PD
is blood-brain barrier (BBB) dysfunction
and, caffeine exerts protective effects against AD and PD
at least in part by keeping the BBB intact.
(more...)

2010.05: Leptin Reduces the Accumulation of
Aβ and Phosphorylated Tau
Induced by 27-Hydroxycholesterol
in Rabbit Organotypic Slices
(Gurdeep Marwarha, Bhanu Dasari1, Jaya R.P. Prasanthi,
Jared Schommer, Othman Ghribi):

Accumulation of amyloid-β (Aβ) peptide
and deposition of hyperphosphorylated tau protein
are two major pathological hallmarks of Alzheimer's disease (AD).
. cholesterol-enriched diets and its metabolite
27-hydroxycholesterol (27-OHC)
increase Aβ and phosphorylated tau levels.
. Leptin, an adipocytokine involved in
cell survival and in learning,
has been demonstrated to regulate
Aβ production and tau hyperphosphorylation
in transgenic mice for AD.
. we examined the involvement of leptin signaling
in tau hyperphosphorylation and
cholesterol/metabolites-induced Aβ accumulation:
. feeding rabbits a 2% cholesterol-enriched diet
for 12 weeks, reduces the levels of leptin by 80%
and incubating rabbit hippocampus with 27-OHC
reduced leptin levels by 30%.
Treatment with leptin reversed the 27-OHC-induced increase in
Aβ and phosphorylated tau
by decreasing the levels of BACE-1 and GSK-3β respectively.
Our results suggest that cholesterol-enriched diets
and cholesterol metabolites induce AD-like pathology
by altering leptin signaling.
2012.01: Cholesterol Increases Ventricular Volume
in a Rabbit Model of Alzheimer's Disease
(Stephen Deci, Susan K. Lemieux, Carrie A. Smith-Bell,
D. Larry Sparks, Bernard G. Schreurs):

One of the hallmarks of Alzheimer's disease
is a significant increase in ventricular volume.
To date we and others have shown that a cholesterol-fed
rabbit model of Alzheimer's disease
displays as many as fourteen different
pathological markers of Alzheimer's disease
including amyloid-β accumulation, thioflavin-S staining,
blood brain barrier breach, microglia activation,
cerebrovasculature changes,
and alterations in learning and memory.
. we now report that cholesterol-fed rabbits also show
a significant increase in ventricular volume
following 10 weeks on a diet of 2% cholesterol.
The increase in volume is attributable in large part
to increases in the size of the third ventricle.
These changes are accompanied by significant increases in
the number of amyloid-β immuno-positive cells
in the cortex and hippocampus.
Increases in the number of amyloid-β neurons
in the cortex also occurred with the addition of
0.24 ppm copper [a pro-oxidant] to the drinking water.
Together with a list of other pathological markers,
the current results add further validity to
the value of the cholesterol-fed rabbit as a
non-transgenic animal model of Alzheimer's disease.
2012.03: Deferiprone Reduces
Amyloid-β and Tau Phosphorylation Levels
but not Reactive Oxygen Species Generation
in Hippocampus of Rabbits Fed a Cholesterol-Enriched Diet
(Jaya R.P. Prasanthi, Matthew Schrag, Bhanu Dasari1,
Gurdeep Marwarha, Wolff M. Kirsch, Othman Ghribi):

. Accumulation of amyloid-β (Aβ) peptide
and the hyperphosphorylation of tau protein
are major hallmarks of Alzheimer's disease (AD).
Additionally, altered metabolism of iron
may have a role in the pathogenesis of AD.
We have previously demonstrated that
cholesterol-enriched diet causes AD-like pathology
with iron deposition in rabbit brain.
. we administered the iron chelator deferiprone
in drinking water to rabbits fed with
a 2% cholesterol diet for 12 weeks.
We found that deferiprone (both at 10 and 50 mg/kg/day)
significantly decreased levels of Aβ40 and Aβ42
as well as BACE1, the enzyme that initiates
cleavage of amyloid-β protein precursor to yield Aβ.
Deferiprone also reduced the cholesterol diet-induced
increase in phosphorylation of tau
but failed to reduce reactive oxygen species generation.
While deferiprone treatment was not associated with
any change in brain iron levels,
it was associated with a significant reduction in plasma iron
and cholesterol levels.
--[my comment:
. how did the iron chelator lower cholesterol?
is it possible that the entire therapeutic effect
came from lowering cholesterol ?
. the same author attributed the effects of caffeine
to blood brain barrier, but didn't mention
caffeine is an anti-diabetic .