Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

Autor: Daniel M. Michaelson, Amir Dori, Joab Chapman, Shiran Salomon-Zimri, Amit Koren-Iton, Efrat Shavit-Stein, Alex Smolar
Rok vydání: 2020
Předmět:
Apolipoprotein E
Pathology
hippocampus
targeted replacement (tr) mice
Apolipoprotein E4
Apolipoprotein E3
Hippocampal formation
lcsh:Chemistry
Mice
type 2 diabetes mellitus (t2dm)
high-fat diet (hfd)
insulin resistance
lcsh:QH301-705.5
Spectroscopy
Pain Measurement
Quantitative Biology::Biomolecules
biology
apolipoprotein e4 (apoe4)
Brain
General Medicine
Computer Science Applications
Memory
Short-Term
medicine.anatomical_structure
lipids (amino acids
peptides
and proteins)
Astrophysics::Earth and Planetary Astrophysics
Locomotion
Signal Transduction
medicine.medical_specialty
Genotype
Central nervous system
Mice
Transgenic
Diet
High-Fat
Article
Catalysis
Inorganic Chemistry
Apolipoproteins E
Insulin resistance
Alzheimer Disease
medicine
Animals
Humans
Physical and Theoretical Chemistry
Glycogen synthase
insulin signaling
Molecular Biology
Protein kinase B
business.industry
Organic Chemistry
Type 2 Diabetes Mellitus
Glucose Tolerance Test
medicine.disease
Mice
Inbred C57BL
Insulin receptor
Diabetes Mellitus
Type 2
lcsh:Biology (General)
lcsh:QD1-999
biology.protein
alzheimer’s disease (ad)
business
Proto-Oncogene Proteins c-akt
Zdroj: International Journal of Molecular Sciences, Vol 21, Iss 4, p 1289 (2020)
International Journal of Molecular Sciences
Volume 21
Issue 4
ISSN: 1422-0067
DOI: 10.3390/ijms21041289
Popis: Apolipoprotein E (APOE) &epsilon
4 gene allele and type 2 diabetes mellitus (T2DM) are prime risk factors for Alzheimer&rsquo
s disease (AD). Despite evidence linking T2DM and apoE4, the mechanism underlying their interaction is yet to be determined. In the present study, we employed a model of APOE-targeted replacement mice and high-fat diet (HFD)-induced insulin resistance to investigate diabetic mechanisms associated with apoE4 pathology and the extent to which they are driven by peripheral and central processes. Results obtained revealed an intriguing pattern, in which under basal conditions, apoE4 mice display impaired glucose and insulin tolerance and decreased insulin secretion, as well as cognitive and sensorimotor characteristics relative to apoE3 mice, while the HFD impairs apoE3 mice without significantly affecting apoE4 mice. Measurements of weight and fasting blood glucose levels increased in a time-dependent manner following the HFD, though no effect of genotype was observed. Interestingly, sciatic electrophysiological and skin intra-epidermal nerve fiber density (IENFD) peripheral measurements were not affected by the APOE genotype or HFD, suggesting that the observed sensorimotor and cognitive phenotypes are related to central nervous system processes. Indeed, measurements of hippocampal insulin receptor and glycogen synthase kinase-3&beta
(GSK-3&beta
) activation revealed a pattern similar to that obtained in the behavioral measurements while Akt activation presented a dominant effect of diet. HFD manipulation induced genotype-independent hyperlipidation of apoE, and reduced levels of brain apoE in apoE3 mice, rendering them similar to apoE4 mice, whose brain apoE levels were not affected by the diet. No such effect was observed in the peripheral plasma levels of apoE, suggesting that the pathological effects of apoE4 under the control diet and apoE3 under HFD conditions are related to the decreased levels of brain apoE. Taken together, our data suggests that diabetic mechanisms play an important role in mediating the pathological effects of apoE4 and that consequently, diabetic-related therapy may be useful in treating apoE4 pathology in AD.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje