Evidence for Compromised Insulin Signaling and Neuronal Vulnerability in Experimental Model of Sporadic Alzheimer’s Disease

  • Smriti Gupta
  • Kamalendra Yadav
  • Shrikant S. Mantri
  • Nitin K. Singhal
  • Subramaniam Ganesh
  • Rajat Sandhir
Article

Abstract

Evidence from animal studies categorizes sporadic Alzheimer’s disease (sAD) as a metabolic syndrome with accompanying cognitive deficits. Given that glial cells act as “silent partners” to neurons by providing trophic support and defense, the present study investigated the role of glia in sAD pathology. A streptozotocin (STZ)-induced glial-neuronal co-culture model of sAD was used to study the metabolic status of the two cell types. Real time RT-PCR and Western blotting results indicated that amyloid precursor protein (APP) and β-secretase (BACE1) were highly expressed in co-cultured neurons than in monocultures. Increased amyloidogenesis was accompanied by decreased expression of mediators in insulin signaling pathway that included insulin receptor (IR), insulin receptor substrate 2 (IRS2), insulin-like growth factor 2 (IGF2), insulin-like growth factor 1 receptor (IGF1R), total-glycogen synthase kinase 3β (t-GSK3β), and phosphorylated-GSK3βser9 (p-GSK3βser9), suggesting that neuronal cells are more prone to metabolic variability when cultured in the presence of glial cells. Findings from the sAD model induced by intracerebroventricular (ICV) injection of STZ revealed that increased amyloid beta (Aβ) load in the hippocampus was potentially responsible for the hyperphosphorylation of tau at ser396. Furthermore, impaired cognitive functions and decreased dendritic spine density and axonal thinning in CA1 region of hippocampus were associated with decreased IR and p-GSK3βser9/t-GSK3β expression. Taken together, the present study provides evidence that glia mediated response and insulin signaling defects drive pathological changes in sAD and represent potential targets for delaying sAD progression.

Keywords

Alzheimer’s disease Amyloid precursor protein Beta amyloid Dendritic spines Diabetes Memory Neurofibriallary tangles 

Abbreviations

APP

amyloid precursor protein

ADAM 10

a Disintegrin and metalloproteinase domain-containing protein 10

amyloid beta

aCSF

artificial cerebrospinal fluid

AD

Alzheimer’s disease

BACE1

β-secretase 

BBB

blood-brain barrier

DMEM

Dulbecco’s modified Eagle’s medium

GAPDH

glyceraldehyde-3-phosphate dehydrogenase

GOD-POD

glucose oxidase-peroxidise

GLUT1

glucose transporter 1

GLUT3

glucose transporter 3

ICV

intracerebroventricular

IGF1

insulin like growth factor1

IGF 2

insulin like growth factor2

IGF1R

insulin like growth factor 1 receptor

insr

insulin receptor gene

IP

intraperitoneal

IR

insulin receptor

IRBS

insulin-resistant brain state

IRS1

insulin receptor substrate 1

IRS2

insulin receptor substrate2

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

MWM

Morris water maze

NBDG

2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl, amino)-2-deoxyglucose)

NFTs

neuro-fibrillary tangles

NGF

nerve growth factor

p-GSK3βser9

phospho-glycogen synthase kinase 3 β

PHF

paired helical filament

PKC

protein kinase C

RPMI

Roswell Park Memorial Institute

sAD

sporadic Alzheimer’s disease

SLC2A1

facilitated glucose transporter member 1

SLC2A3

facilitated glucose transporter member 3

STZ

streptozotocin

T3D

type 3 diabetes

t-GSK3β

total-glycogen synthase kinase3β

Notes

Acknowledgements

This work was supported by UGC-BSR fellowship program (Ref. No. F.4-1/2006 [BSR]/7-209/2009 [BSR] and UGC-SAP DRS phase II program (Ref. No. F.4-7/2015/DRS-II (SAP-II). The authors also acknowledge the finacial support from the DST under PURSE (Phase II) grant. The authors thank Ms. Komal Taneja for her support with Golgi-Cox staining.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_985_MOESM1_ESM.pdf (458 kb)
ESM 1 (PDF 458 kb)

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Authors and Affiliations

  1. 1.Department of Biochemistry, Basic Medical Science Block II, Sector 25Panjab UniversityChandigarhIndia
  2. 2.National Agri-Food Biotechnology InstituteMohaliIndia
  3. 3.Department of Biological Sciences and BioengineeringIndian Institute of TechnologyKanpurIndia

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