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Experimental Approach to Alzheimer’s Disease with Emphasis on Insulin Resistance in the Brain

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Abstract

This chapter on current experimental models of Alzheimer’s disease (AD) is based on human post-mortem findings showing keystone markers for pathology within the ß-amyloid transduction cascade as well as pathology in the mechanism of phosphorylation of tau protein. Evidence for risk factors triggering this devastating disease focuses on type II diabetes. Therefore, modeling of Alzheimer’s disease aims to gain profound knowledge of these underlying mechanisms by studying experimental animal models. Here, several pharmacological models will be discussed in detail, with special emphasis on the one mirroring type II diabetes-related AD pathology induced by streptozotocin and its influences on the insulin/insulin receptor cascade in the brain as well as ß-amyloid and tau pathologies associated with cognitive impairments. While most of transgenic mouse models, like the APP Tg2576 model, demonstrate ß-amyloid plaque formation and impaired memory in rather old age, streptozotocin is able to aggravate the process of pathology so that AD pathology is seen months earlier. This indicates a profound interaction of AD pathology with the brain insulin/insulin receptor cascade and pathobiochemistry. Since this interaction is gaining more and more interest, it is here discussed in a view of a non-transgenic modeling of AD introduced lately by means of a central application of synthetic β-amyloid. Recent trend of repurposing antidiabetic drugs as possible anti-AD drugs and beneficial effects of the intranasal insulin therapy both in clinical and preclinical trials provides a strong support to the metabolic/brain insulin dysfunction-related core of sporadic AD.

Keywords

  • Alzheimer’s disease
  • Animal models
  • Streptozotocin
  • Intracerebroventricular
  • Brain insulin resistance
  • Cerebral glucose metabolism
  • Amyloid ß oligomers
  • Corticosterone

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Abbreviations

AChE:

Acetylcholinesterase

AD:

Alzheimer’s disease

Akt/PKB:

Protein kinase B

APOE-4:

Apolipoprotein E4

APP:

Amyloid precursor protein

Aß:

Amyloid ß

AβOs:

Amyloid β oligomers

BACE1:

β-Secretase-1

BBB:

Blood–brain barrier

BDNF:

Brain-derived neurotrophic factor

CAT:

Catalase

CCH:

Chronic carotid hypoperfusion

ChAT:

Choline acetyltransferase

CM:

Cisterna magna

cort:

Corticosterone

cPD3B:

Cyclic phosphodiesterase 3 β

DM:

Diabetes mellitus

EAOD:

Early-onset Alzhemier’s disease

eNOS:

Endothelial nitric oxide synthase

ERK:

Extracellular signal-regulated kinase

FDG-PET:

Fluoro-2-deoxyglucose positron emission tomography

FOXO:

Forkhead box protein O1

GFAP:

Glial fibrillary acidic protein

GLP-1:

Glucagon-like peptide 1

GLUT2:

Glucose transporter 2

GSK3ß:

Glycogen synthase kinase-3ß

HPA:

Hypothalamic-pituitary-adrenal axis

IDE:

Insulin-degrading enzyme

IR:

Insulin receptor

IRS1:

Insulin receptor substrate-1

JNK1:

c-Jun N terminal kinase 1

LOAD:

Late-onset Alzheimer’s disease

MAPK:

Mitogen-activated protein kinase

MDA:

Malondialdehyde

mEAOD:

Mendelian early-onset Alzheimer’s disease

MEK:

MAP/ERK kinase

mTOR:

The mammalian target of rapamycin

NO:

Nitric oxide

p:

Phosphorylation

P70S6:

Ribosomal protein S6 kinase and its substrate ribosomal protein S6

PHF1:

Paired helical filaments 1

PI3K:

Phosphoinositide 3 kinase

PP1/2 A:

Protein phosphatase 1/2 A

PSEN1/2:

Presenilin 1/2

RAF:

Proto-oncogene serine/threonine-protein kinase

Ras:

Ras protein family

sAD:

Sporadic Alzheimer’s disease

SOD:

Superoxide dismutase

SOS:

Son of sevenless

STZ:

Streptozotocin

STZ-icv:

Streptozotocin-intracerebroventricular

T2DM:

Type 2 diabetes mellitus

tg:

Transgenic

TNF-R:

Tumor necrosis factor receptor

ULK:

Unc-51-like autophagy activating kinase

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Correspondence to Peter Riederer .

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The chapter is dedicated to the memory of Professor Sigfried Hoyer, the coauthor of the original version of this chapter in the first edition of the Textbook, who introduced streptozotocin rat model as a model for sporadic Alzheimer’s disease and proposed the hypothesis of dysfunctional insulin and glucose homeostasis in the brain as its etiopathogenic core.

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Salkovic-Petrisic, M., Perhoc, A.B., Homolak, J., Knezovic, A., Osmanovic Barilar, J., Riederer, P. (2021). Experimental Approach to Alzheimer’s Disease with Emphasis on Insulin Resistance in the Brain. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-030-71519-9_98-1

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