S
Here is the abstract to the above health news report.
The difficult finding to understand is how come GSK3-beta activity
*increases* in the face of *decreasing* "insulin and insulin-like
growth factor type I and II (IGF-I and IGF-II) signaling mechanisms in
*brains with AD*".
A new study [see #2 below] asks the very same question. It found that
GSK3 level in mouse brain has to do with the level of *blood glucose*
and not only insulin signalling: "Long term hyperglycemia also
increased brain Akt and GSK3 phosphorylation, both 4 weeks after
streptozotocin and in db/db insulin-resistant mice."
[Full paper is available at:
http://www.jbc.org/cgi/reprint/M508824200v1]
Arbor
1. J Alzheimers Dis. 2005 Feb;7(1):63-80.
Impaired insulin and insulin-like growth factor expression and
signaling mechanisms in Alzheimer's disease--is this type 3 diabetes?
Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ,
Wands JR, de la Monte SM.
Department of Pathology, Rhode Island Hospital and Brown Medical
School, Providence, RI 02903, USA.
The neurodegeneration that occurs in sporadic Alzheimer's disease (AD)
is consistently associated with a number of characteristic
histopathological, molecular, and biochemical abnormalities, including
cell loss, abundant neurofibrillary tangles and dystrophic neurites,
amyloid-beta deposits, increased activation of pro-death genes and
signaling pathways, impaired energy metabolism/mitochondrial function,
and evidence of chronic oxidative stress. The general inability to
convincingly link these phenomena has resulted in the emergence and
propagation of various heavily debated theories that focus on the role
of one particular element in the pathogenesis of all other
abnormalities. However, the accumulating evidence that reduced glucose
utilization and deficient energy metabolism occur early in the course
of disease, suggests a role for impaired insulin signaling in the
pathogenesis of AD. The present work demonstrates extensive
abnormalities in insulin and insulin-like growth factor type I and II
(IGF-I and IGF-II) signaling mechanisms in brains with AD, and shows
that while each of the corresponding growth factors is normally made in
central nervous system (CNS) neurons, the expression levels are
markedly reduced in AD. These abnormalities were associated with
reduced levels of insulin receptor substrate (IRS) mRNA, tau mRNA,
IRS-associated phosphotidylinositol 3-kinase, and phospho-Akt
(activated), and increased glycogen synthase kinase-3beta activity and
amyloid precursor protein mRNA expression. The strikingly reduced CNS
expression of genes encoding insulin, IGF-I, and IGF-II, as well as the
insulin and IGF-I receptors, suggests that AD may represent a
neuro-endocrine disorder that resembles, yet is distinct from diabetes
mellitus. Therefore, we propose the term, "Type 3 Diabetes" to reflect
this newly identified pathogenic mechanism of neurodegeneration.
PMID: 15750215 [PubMed - indexed for MEDLINE]
2. J Biol Chem. 2005 Dec 2;280(48):39723-31. Epub 2005 Sep 22.
Physiological and pathological changes in glucose regulate brain akt
and glycogen synthase kinase-3.
Clodfelder-Miller B, De Sarno P, Zmijewska AA, Song L, Jope RS.
Department of Psychiatry and Behavioral Neurobiology, University of
Alabama at Birmingham, Birmingham, Alabama 35294-0017.
Insulin regulates the phosphorylation and activities of Akt and
glycogen synthase kinase-3 (GSK3) in peripheral tissues, *but in the
brain it is less clear how this signaling pathway is regulated in vivo
and whether it is affected by diabetes. We found that Akt and GSK3 are
sensitive to glucose, because fasting decreased and glucose
administration increased by several fold the phosphorylation of Akt and
GSK3 in the cerebral cortex and hippocampus of non-diabetic mice. Brain
Akt and GSK3 phosphorylation also increased after streptozotocin
administration (3 days), which increased blood glucose and depleted
blood insulin, *indicating regulation by glucose availability even with
deficient insulin. Changes in Akt and GSK3 phosphorylation and
activities in epididymal fat were opposite to those of brain after
streptozotocin treatment. Streptozotocin-induced hyperglycemia and
increased brain Akt and GSK3 phosphorylation were reversed by lowering
blood glucose with insulin administration. Long term hyperglycemia also
increased brain Akt and GSK3 phosphorylation, both 4 weeks after
streptozotocin and in db/db insulin-resistant mice. Thus, the Akt-GSK3
signaling pathway is regulated in mouse brain in vivo in response to
physiological and pathological changes in insulin and glucose.
PMID: 16179343 [PubMed - in process]
The difficult finding to understand is how come GSK3-beta activity
*increases* in the face of *decreasing* "insulin and insulin-like
growth factor type I and II (IGF-I and IGF-II) signaling mechanisms in
*brains with AD*".
A new study [see #2 below] asks the very same question. It found that
GSK3 level in mouse brain has to do with the level of *blood glucose*
and not only insulin signalling: "Long term hyperglycemia also
increased brain Akt and GSK3 phosphorylation, both 4 weeks after
streptozotocin and in db/db insulin-resistant mice."
[Full paper is available at:
http://www.jbc.org/cgi/reprint/M508824200v1]
Arbor
1. J Alzheimers Dis. 2005 Feb;7(1):63-80.
Impaired insulin and insulin-like growth factor expression and
signaling mechanisms in Alzheimer's disease--is this type 3 diabetes?
Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ,
Wands JR, de la Monte SM.
Department of Pathology, Rhode Island Hospital and Brown Medical
School, Providence, RI 02903, USA.
The neurodegeneration that occurs in sporadic Alzheimer's disease (AD)
is consistently associated with a number of characteristic
histopathological, molecular, and biochemical abnormalities, including
cell loss, abundant neurofibrillary tangles and dystrophic neurites,
amyloid-beta deposits, increased activation of pro-death genes and
signaling pathways, impaired energy metabolism/mitochondrial function,
and evidence of chronic oxidative stress. The general inability to
convincingly link these phenomena has resulted in the emergence and
propagation of various heavily debated theories that focus on the role
of one particular element in the pathogenesis of all other
abnormalities. However, the accumulating evidence that reduced glucose
utilization and deficient energy metabolism occur early in the course
of disease, suggests a role for impaired insulin signaling in the
pathogenesis of AD. The present work demonstrates extensive
abnormalities in insulin and insulin-like growth factor type I and II
(IGF-I and IGF-II) signaling mechanisms in brains with AD, and shows
that while each of the corresponding growth factors is normally made in
central nervous system (CNS) neurons, the expression levels are
markedly reduced in AD. These abnormalities were associated with
reduced levels of insulin receptor substrate (IRS) mRNA, tau mRNA,
IRS-associated phosphotidylinositol 3-kinase, and phospho-Akt
(activated), and increased glycogen synthase kinase-3beta activity and
amyloid precursor protein mRNA expression. The strikingly reduced CNS
expression of genes encoding insulin, IGF-I, and IGF-II, as well as the
insulin and IGF-I receptors, suggests that AD may represent a
neuro-endocrine disorder that resembles, yet is distinct from diabetes
mellitus. Therefore, we propose the term, "Type 3 Diabetes" to reflect
this newly identified pathogenic mechanism of neurodegeneration.
PMID: 15750215 [PubMed - indexed for MEDLINE]
2. J Biol Chem. 2005 Dec 2;280(48):39723-31. Epub 2005 Sep 22.
Physiological and pathological changes in glucose regulate brain akt
and glycogen synthase kinase-3.
Clodfelder-Miller B, De Sarno P, Zmijewska AA, Song L, Jope RS.
Department of Psychiatry and Behavioral Neurobiology, University of
Alabama at Birmingham, Birmingham, Alabama 35294-0017.
Insulin regulates the phosphorylation and activities of Akt and
glycogen synthase kinase-3 (GSK3) in peripheral tissues, *but in the
brain it is less clear how this signaling pathway is regulated in vivo
and whether it is affected by diabetes. We found that Akt and GSK3 are
sensitive to glucose, because fasting decreased and glucose
administration increased by several fold the phosphorylation of Akt and
GSK3 in the cerebral cortex and hippocampus of non-diabetic mice. Brain
Akt and GSK3 phosphorylation also increased after streptozotocin
administration (3 days), which increased blood glucose and depleted
blood insulin, *indicating regulation by glucose availability even with
deficient insulin. Changes in Akt and GSK3 phosphorylation and
activities in epididymal fat were opposite to those of brain after
streptozotocin treatment. Streptozotocin-induced hyperglycemia and
increased brain Akt and GSK3 phosphorylation were reversed by lowering
blood glucose with insulin administration. Long term hyperglycemia also
increased brain Akt and GSK3 phosphorylation, both 4 weeks after
streptozotocin and in db/db insulin-resistant mice. Thus, the Akt-GSK3
signaling pathway is regulated in mouse brain in vivo in response to
physiological and pathological changes in insulin and glucose.
PMID: 16179343 [PubMed - in process]