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

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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.

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Abbreviations

APP:

amyloid precursor protein

ADAM 10:

a Disintegrin and metalloproteinase domain-containing protein 10

Aβ:

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

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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.

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Authors and Affiliations

  1. Department of Biochemistry, Basic Medical Science Block II, Sector 25, Panjab University, Chandigarh, 160014, India

    Smriti Gupta & Rajat Sandhir

  2. National Agri-Food Biotechnology Institute, Sector 81, S.A.S. Nagar, Mohali, Punjab, 140306, India

    Kamalendra Yadav, Shrikant S. Mantri & Nitin K. Singhal

  3. Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, 208016, India

    Subramaniam Ganesh

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  1. Smriti Gupta
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Correspondence to Rajat Sandhir.

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Gupta, S., Yadav, K., Mantri, S.S. et al. Evidence for Compromised Insulin Signaling and Neuronal Vulnerability in Experimental Model of Sporadic Alzheimer’s Disease. Mol Neurobiol 55, 8916–8935 (2018). https://doi.org/10.1007/s12035-018-0985-0

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