Transcript Alzheimer`s Disease is Type 3 Diabetes

Alzheimer's Disease is Type 3
Diabetes- Evidence Reviewed
BY: SUZANNE DE LA MONTE, M.D. &
JACK WARDS, M.D.
PRESENTED BY: CAITLAN
BLYDENBURGH
Introduction
 5.4 million Americans are living with Alzheimer's
disease.
 25.8 million children and adults in the United
States—8.3% of the population—have diabetes.
Introduction
 Alzheimer's disease is a progressive neurologic
disease of the brain which leads to the irreversible
loss of neurons and the loss of intellectual abilities,
including memory and reasoning
Introduction
 Diabetes, describes a group of metabolic diseases in
which the person has high blood glucose (blood
sugar), either because insulin production is
inadequate, or because the body's cells do not
respond properly to insulin, or both.
What is insulin?
 Insulin is a hormone that is produced by the beta
cells

Beta Cells- are cells that are scattered throughout the pancreas.
 The insulin produced is released into the blood
stream and travels throughout the body.
 Insulin is an important hormone that has many
“jobs” within the body. Most of the actions of insulin
are directed at metabolism of carbohydrates, lipids,
and proteins.
What is insulin resistance?
 Insulin resistance is a condition where the cells of
the body become resistant to the effects of insulin

that is, the normal response to a given amount of insulin is
reduced.
 As a result, higher levels of insulin are needed in
order for insulin to have its effects.
Introduction
 Alzheimer's is being called a neuroendocrine disease
because it involves insulin resistance in the brain.
Insulin In the Brain
Why is insulin needed in the Brain?
 Like other cells in the body, neurons in the brain
need glucose to fuel their activities.
Insulin in the Brain
 In the brain, insulin has a number of roles to play.
It promotes glucose uptake in the neurons of the hippocampal
formation and the frontal lobes, areas that are involved in
memory.
 It strengthens the synaptic connections between brain cells,
helping to form new memories.
 It regulates the neurotransmitter acetylcholine, which plays an
important role in learning and memory.

Synapse
http://science.cabot.ac.uk/?p=1427
Review of Literature
 de la Monte SM, Wands JR. Review of insulin and insulin-like growth
factor expression, signaling, and malfunction in the central nervous
system: relevance to Alzheimer's disease. J Alzheimers Dis.
2005;7(1):45–61.

There are biochemical, molecular, and cellular abnormalities
that come with AD neurodegeneration. These abnormalities
include increased activation of signaling pathways, impaired
energy metabolism, mitochondrial dysfunction, chronic
oxidative stress, and DNA damage.
Review of Literature
 Hoyer S. Causes and consequences of disturbances of cerebral glucose
metabolism in sporadic Alzheimer disease: therapeutic implications.
Adv Exp Med Biol. 2004;541:135–152.

Under scientific evaluation researchers have found that
impairments in cerebral glucose consumption, and energy
metabolism represent early abnormalities that occur before or
during the initial stages in AD.
Review of Literature
 Virkamäki A, Ueki K, Kahn CR. Protein-protein interaction in insulin
signaling and the molecular mechanisms of insulin resistance. J Clin
Invest. 1999;103(7):931–943.


This led researchers to the concept that impaired insulin
signaling plays a important role in the pathogenesis of AD.
All of the correlations drawn can help to show that AD
represents “type 3 diabetes”.
Hypothesis
 If Alzheimer's Disease represents a form of diabetes
mellitus then it may cause selective abnormalities in
the brain, and there for can be referred to as type 3
diabetes.
Methods and Materials
 Researchers utilized experimental models to
demonstrate that diabetes mellitus- type molecular
and biochemical abnormalities could be produced in
CNS neurons and the brain through exposure to
Streptozotocin (STZ).
 Streptozotocin (STZ) is a drug that causes diabetes
because it is taken up by insulin- producing cells.
Methods and Materials
 Mice were treated with a single intracerebral (ic)
injection of STZ, and were allowed to grow older for
4 weeks.
 The mice were then subjected to Morris water maze
tests of spatial learning and memory, and their
brains were examined for biochemical, and
molecular indices of AD- type neurodegeneration.
Methods and Materials
 After the 4 weeks, from the time when the mice were
given the STZ researchers found molecular,
biochemical, and neuroanatomical pathologies that
are associated with AD.
 This led researchers to test the hypotheses that ADType neurodegeneration could be reduced or
prevented through early treatment with insulinsensitizer antidiabetes agents such as peroxisome
proliferator- activated receptor (PPAR)
agonists.
Methods and Materials
 Peroxisome proliferator-activated receptor agonists
function at the level of the nucleus to activate
insulin-responsive genes and signaling mechanisms.

It’s a drug used to help treat T2DM.
Methods and Materials
 The experimental design involved treating rats with
ic-STZ, followed by a single intraperitoneal injection
of saline, PPAR-α, PPAR-δ, or PPAR-γ activator.
 The doses used were considerably lower than those
routinely given to treat T2DM.
 The planned major effects of the PPAR agonist
treatments were to prevent brain atrophy, preserve
insulin and IGF-2 receptors, prevent deficits in
learning and memory.
Methods and Materials
 Water Maze test to see if the drug worked. After the
single intraperitoneal injection of saline, PPAR-α,
PPAR-δ, or PPAR-γ activator, the mice then retook
the Morris
Results
 The ic- STZ injected mice did not have elevated
blood glucose or insulin levels
 But the brains showed striking evidence of
neurodegeneration.

They showed neuronal and oligodendroglia cell loss and
cerebral atrophy.
• OLIGODENDROGLIA- ARE CELLS FOUND IN THE CENTRAL
NERVOUS SYSTEM
 Loss of oligodendroglia could contribute to the early
white matter degeneration and synaptic
disconnection, which is shown in the early stages of
AD.
Results
 The compared results from the first Morris Water
Maze test (after ic-STZ injection) and the second
(after PPAR injection) test showed a significant
improvement in learning and spatial memory tasks.
Results
Discussion
 The results from this study provided evidence that
AD represents a form of diabetes mellitus that
selectively afflicts the brain.
 The results of the Morris Water Maze tests, showed
how the antidiabetes drug reduced typical
characteristics of AD, which helped to show how AD
mimics certain parts of Diabetes.
Discussion
 The data provided strong evidence that AD is
intrinsically a neuroendocrine disease caused by
selective impairments in insulin and IGF signaling
mechanisms, including deficiencies in local insulin
and IGF production.
Conclusion
 Therefore referring to AD as T3DM is justified,
because the fundamental molecular and biochemical
abnormalities overlap with T1DM and T2DM rather
than mimic the effects of either one.
Acknowledgements
 Ms. Gleason
 Older Science Research students
 Friends and family
 My Cousin Brooke
References












1. Jalbert JJ, Daiello LA, Lapane KL. Dementia of the Alzheimer Type. Epidemiol Rev. 2008 [Epub ahead of print.]
2. Jellinger KA. Neuropathological aspects of Alzheimer disease, Parkinson disease and frontotemporal dementia. Neurodegener
Dis. 2008;5(3-4):118–121. [PubMed]
3. Wang XP, Ding HL. Alzheimer's disease: epidemiology, genetics, and beyond. Neurosci Bull. 2008;24(2):105–109. [PubMed]
4. de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the
central nervous system: relevance to Alzheimer's disease. J Alzheimers Dis. 2005;7(1):45–61. [PubMed]
5. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM. Impaired insulin and
insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease—is this type 3 diabetes? J Alzheimers Dis.
2005;7(1):63–80. [PubMed]
6. de la Monte SM, Wands JR. Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress
with severity of Alzheimer's disease. J Alzheimers Dis. 2006;9(2):167–181. [PubMed]
7. Moreira PI, Santos MS, Seiça R, Oliveira CR. Brain mitochondrial dysfunction as a link between Alzheimer's disease and
diabetes. J Neurol Sci. 2007;257(1-2):206–214. [PubMed]
8. Hoyer S. The brain insulin signal transduction system and sporadic (type II) Alzheimer disease: an update. J Neural Transm.
2002;109(3):341–360. [PubMed]
9. Nixon RA. The calpains in aging and aging-related diseases. Ageing Res Rev. 2003;2(4):407–418. [PubMed]
10. Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM. Insulin and insulin-like growth factor expression and
function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine. J Alzheimers Dis.
2005;8(3):247–268. [PubMed]
11. Revill P, Moral MA, Prous JR. Impaired insulin signaling and the pathogenesis of Alzheimer's disease. Drugs Today (Barc)
2006;42(12):785–790. [PubMed]
12. Iwangoff P, Armbruster R, Enz A, Meier-Ruge W. Glycolytic enzymes from human autoptic brain cortex: normal aged and
demented cases. Mech Ageing Dev. 1980;14(1-2):203–209. [PubMed]
References












13. Sims NR, Bowen DM, Smith CC, Flack RH, Davison AN, Snowden JS, Neary D. Glucose metabolism and acetylcholine
synthesis in relation to neuronal activity in Alzheimer's disease. Lancet. 1980;1(8164):333–336. [PubMed]
14. Hoyer S. Causes and consequences of disturbances of cerebral glucose metabolism in sporadic Alzheimer disease: therapeutic
implications. Adv Exp Med Biol. 2004;541:135–152. [PubMed]
15. Virkamäki A, Ueki K, Kahn CR. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin
resistance. J Clin Invest. 1999;103(7):931–943. [PMC free article] [PubMed]
16. Alvarez-Martínez H, Pérez-Campos E. [Non-alcoholic steatohepatitis] Rev Gastroenterol Mex. 2002;67(2):118–125. [PubMed]
17. Solís Herruzo JA, García Ruiz I, Pérez Carreras M, Muñoz Yagüe MT. Non-alcoholic fatty liver disease. From insulin resistance
to mitochondrial dysfunction. Rev Esp Enferm Dig. 2006;98(11):844–874. [PubMed]
18. Saito T, Misawa K, Kawata S. 1 Fatty liver and non-alcoholic steatohepatitis. Intern Med. 2007;46(2):101–103. [PubMed]
19. Craft S, Asthana S, Cook DG, Baker LD, Cherrier M, Purganan K, Wait C, Petrova A, Latendresse S, Watson GS, Newcomer JW,
Schellenberg GD, Krohn AJ. Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer's
disease: interactions with apolipoprotein-E genotype. Psychoneuroendocrinology. 2003;28(6):809–822. [PubMed]
20. Craft S, Asthana S, Schellenberg G, Baker L, Cherrier M, Boyt AA, Martins RN, Raskind M, Peskind E, Plymate S. Insulin
effects on glucose metabolism, memory, and plasma amyloid precursor protein in Alzheimer's disease differ according to
apolipoprotein-E genotype. Ann N Y Acad Sci. 2000;903:222–228. [PubMed]
21. Farris W, Mansourian S, Leissring MA, Eckman EA, Bertram L, Eckman CB, Tranzi RE, Selkoe DJ. Partial loss-of-function
mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein. Am J Pathol.
2004;164(4):1425–1434. [PMC free article] [PubMed]
22. Hoyer S. Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol. 2004;490(13):115–125. [PubMed]
23. Schubert M, Brazil DP, Burks DJ, Kushner JA, Ye J, Flint CL, Farhang-Fallah J, Dikkes P, Warot XM, Rio C, Corfas G, White
MF. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci.
2003;23(18):7084–7092. [PubMed]
24. Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D, Kondo T, Alber J, Galldiks N, Küstermann E, Arndt S, Jacobs
AH, Krone W, Kahn CR, Brüning JC. Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci U S A.
2004;101(9):3100–3105. [PMC free article] [PubMed]
References












25. Craft S. Insulin resistance and cognitive impairment: a view through the prism of epidemiology. Arch Neurol.
2005;62(7):1043–1044. [PubMed]
26. Craft S. Insulin resistance syndrome and Alzheimer disease: pathophysiologic mechanisms and therapeutic implications.
Alzheimer Dis Assoc Disord. 2006;20(4):298–301. [PubMed]
27. Craft S. Insulin resistance and Alzheimer's disease pathogenesis: potential mechanisms and implications for treatment. Curr
Alzheimer Res. 2007;4(2):147–152. [PubMed]
28. de la Monte SM, Tong M, Lester-Coll N, Plater M, Jr, Wands JR. Therapeutic rescue of neurodegeneration in experimental
type 3 diabetes: relevance to Alzheimer's disease. J Alzheimers Dis. 2006;10(1):89–109. [PubMed]
29. Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM. Intracerebral streptozotocin model of type 3
diabetes: relevance to sporadic Alzheimer's disease. J Alzheimers Dis. 2006;9(1):13–33. [PubMed]
30. de la Monte SM, Ganju N, Banerjee K, Brown NV, Luong T, Wands JR. Partial rescue of ethanol-induced neuronal apoptosis
by growth factor activation of phosphoinositol-3-kinase. Alcohol Clin Exp Res. 2000;24(5):716–726. [PubMed]
31. de la Monte SM, Neely TR, Cannon J, Wands JR. Ethanol impairs insulin-stimulated mitochondrial function in cerebellar
granule neurons. Cell Mol Life Sci. 2001;58(12-13):1950–1960. [PubMed]
32. de la Monte SM, Wands JR. Chronic gestational exposure to ethanol impairs insulin-stimulated survival and mitochondrial
function in cerebellar neurons. Cell Mol Life Sci. 2002;59(5):882–893. [PubMed]
33. Xu J, Yeon JE, Chang H, Tison G, Chen GJ, Wands J, de la Monte S. Ethanol impairs insulin-stimulated neuronal survival in
the developing brarole of PTEN phosphatase. J Biol Chem. 2003;278(29):26929–26937. [PubMed]
34. Myers MG, Sun XJ, White MF. The IRS-1 signaling system. Trends Biochem Sci. 1994;19(7):289–293. [PubMed]
35. O'Hare T, Pilch PF. Intrinsic kinase activity of the insulin receptor. Int J Biochem. 1990;22(4):315–324. [PubMed]
36. Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli LM, Dull TJ, Gray A, Coussens L, Liao YC, Tsubokawa M, et al. Human
insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature. 1985;313(6005):756–761. [PubMed]
References












37. Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA, Cahill DA, Goldstein BJ, White MF. Structure of the insulin receptor
substrate IRS-1 defines a unique signal transduction protein. Nature. 1991;352(6330):73–77. [PubMed]
38. White MF, Maron R, Kahn CR. Insulin rapidly stimulates tyrosine phosphorylation of a Mr-185,000 protein in intact cells.
Nature. 1985;318(6042):183–186. [PubMed]
39. Sun XJ, Crimmins DL, Myers MJ, Jr, Miralpeix M, White MF. Pleiotropic insulin signals are engaged by multisite
phosphorylation of IRS-1. Mol Cell Biol. 1993;13(12):7418–7428. [PMC free article] [PubMed]
40. Burgering BM, Coffer PJ. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature.
1995;376(6541):599–602. [PubMed]
41. Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S. Phosphoinositide-3-OH kinase-dependent regulation of
glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci U S A. 1998;95(19):11211–
11216. [PMC free article] [PubMed]
42. Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME. Regulation of
neuronal survival by the serine-threonine protein kinase Akt. Science. 1997;275(5300):661–665. [See comments.] [PubMed]
43. Kulik G, Klippel A, Weber MJ. Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3kinase, and Akt. Mol Cell Biol. 1997;17(3):1595–1606. [PMC free article] [PubMed]
44. Lam K, Carpenter CL, Ruderman NB, Friel JC, Kelly KL. The phosphatidylinositol 3-kinase serine kinase phosphorylates IRS 1.
Stimulation by insulin and inhibition by Wortmannin. J Biol Chem. 1994;269(32):20648–20652. [PubMed]
45. Mill JF, Chao MV, Ishii DN. Insulin, insulin-like growth factor II, and nerve growth factor effects on tubulin mRNA levels and
neurite formation. Proc Natl Acad Sci U S A. 1985;82(20):7126–7130. [PMC free article] [PubMed]
46. Puro DG, Agardh E. Insulin-mediated regulation of neuronal maturation. Science. 1984;225(4667):1170–1172. [PubMed]
47. Pasquier F, Boulogne A, Leys D, Fontaine P. Diabetes mellitus and dementia. Diabetes Metab. 2006;32(5 Pt 1):403–414.
[PubMed]
48. Verdelho A, Madureira S, Ferro JM, Basile AM, Chabriat H, Erkinjuntti T, Fazekas F, Hennerici M, O'Brien J, Pantoni L,
Salvadori E, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D. LADIS Study. Differential impact of cerebral
white matter changes, diabetes, hypertension and stroke on cognitive performance among non-disabled elderly. The LADIS study.
J Neurol Neurosurg Psychiatry. 2007;78(12):1325–1330. [PMC free article] [PubMed]
Questions?