Long-term effects of intracranial islet grafting on cognitive functioning in a rat metabolic model of sporadic Alzheimer's disease-like dementia

Autoři: Konstantin Bloch aff001;  Shay Henry Hornfeld aff002;  Shira Dar aff002;  Alexey Vanichkin aff003;  Irit Gil-Ad aff002;  Pnina Vardi aff001;  Abraham Weizman aff002
Působiště autorů: Laboratory of Diabetes and Obesity Research, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel aff001;  Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel aff002;  Laboratory of Transplantation, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel aff003;  Research Unit, Geha Mental Health Center, Petah Tikva, Israel aff004
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0227879


Accumulating evidence suggests that Alzheimer’s disease is associated with brain insulin resistance, as are some other types of dementia. Intranasal insulin administration has been suggested as a potential approach to overcoming brain insulin resistance and improving cognitive functions. Islet transplantation into the cranial subarachnoid cavity was used as an alternative route for insulin delivery into the brain. Recently, the authors showed the short-term beneficial cognitive effect of a small number of intracranially grafted islets in rats with cognitive dysfunction induced by intracerebroventricular administration of streptozotocin (icv-STZ). This was associated with continuous and safe insulin delivery to the rat brain. The current study investigated the long-term effect of intracranial grafting of islets on cognitive functioning in icv-STZ rats. Severe dementia, associated with obesity and cerebral amyloid-β angiopathy, was induced in Lewis inbred rats by icv-STZ. Two months after icv-STZ, one hundred syngeneic islets were transplanted into the cranial subarachnoid space. Two and six months later, cognitive alterations were assessed by Morris water-maze tests. Islet graft survival was evaluated by immunohistochemical and biochemical assays. Improvement was found in spatial learning and memory of grafted rats as opposed to the sham-operated icv-STZ rats. The grafted islets showed intact morphology, intensive expression of insulin, glucagon and glucose transporter 2. Normoglycemic obesity and cerebral amyloid-β angiopathy were found in both grafted and sham-operated icv-STZ rats. In conclusion, islet grafting into cranial subarachnoid space provides an efficient and safe approach for insulin delivery to the brain, leading to a long-term attenuation of icv-STZ-induced cognitive dysfunction.

Klíčová slova:

Alzheimer's disease – Animal cognition – Body weight – Cerebrospinal fluid – Cognitive impairment – Enzyme-linked immunoassays – Insulin – Obesity


1. Arnold SE, Arvanitakis Z, Macauley-Rambach SL, Koenig AM, Wang HY, Ahima RS, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol. 2018;14:168–181. doi: 10.1038/nrneurol.2017.185 29377010

2. Stoeckel LE, Arvanitakis Z, Gandy S, Small D, Kahn CR, Pascual-Leone A, et al. Complex mechanisms linking neurocognitive dysfunction to insulin resistance and other metabolic dysfunction. Version 2. F1000Res. 2016 Mar 15 [revised 2016 Jun 2];5:353. doi: 10.12688/f1000research.8300.2 27303627

3. Duelli R, Schröck H, Kuschinsky W, Hoyer S. Intracerebroventricular injection of streptozotocin induces discrete local changes in cerebral glucose utilization in rats. Int J Dev Neurosci. 1994; 12:737–743. doi: 10.1016/0736-5748(94)90053-1 7747600

4. Salkovic-Petrisic M, Knezovic A, Hoyer S, Riederer P. What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer's disease, about the therapeutic strategies in Alzheimer's research. J Neural Transm. 2013; 120:233–252. doi: 10.1007/s00702-012-0877-9 22886150

5. Grieb P. Intracerebroventricular streptozotocin injections as a model of Alzheimer's disease: in search of a relevant mechanism. Mol Neurobiol. 2016; 53:1741–1752. doi: 10.1007/s12035-015-9132-3 25744568

6. Bloch K, Gil-Ad I, Vanichkin A, Hornfeld SH, Koroukhov N, Taler M, et al. Intracerebroventricular streptozotocin induces obesity and dementia in Lewis rats. J Alzheimer's Dis. 2017; 60:121–136.

7. Bloch K, Gil-Ad I, Vanichkin A, Hornfeld SH, Taler M, Dar S, et al. Intracranial transplantation of pancreatic islets attenuates cognitive and peripheral metabolic dysfunctions in a rat model of sporadic Alzheimer's disease. J Alzheimer's Dis. 2018; 65:1445–1458.

8. Rhea EM, Salameh TS, Banks WA. Routes for the delivery of insulin to the central nervous system: A comparative review. Exp Neurol. 2019;313:10–15. doi: 10.1016/j.expneurol.2018.11.007 30500332

9. Freiherr J, Hallschmid M, Frey WH 2nd, Brünner YF, Chapman CD, Hölscher C, et al. Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence. CNS Drugs. 2013; 27:505–514. doi: 10.1007/s40263-013-0076-8 23719722

10. Craft S, Claxton A, Baker LD, Hanson AJ, Cholerton B, Trittschuh EH, et al. Effects of regular and long-acting insulin on cognition and Alzheimer's disease biomarkers: A Pilot Clinical Trial. J Alzheimer's Dis. 2017;57:1325–1334.

11. Bloch K, Vanichkin A, Gil-Ad I, Vardi P, Weizman A. Insulin delivery to the brain using intracranial implantation of alginate-encapsulated pancreatic islets. J Tissue Eng Regen Med. 2017;11: 3263–3272. doi: 10.1002/term.2235 28127888

12. Bloch K, Gil-Ad I, Tarasenko I, Vanichkin A, Taler M, Hornfeld SH, et al. Intracranial pancreatic islet transplantation increases islet hormone expression in the rat brain and attenuates behavioral dysfunctions induced by MK-801 (dizocilpine). Horm Behav. 2015;72:1–11. doi: 10.1016/j.yhbeh.2015.04.019 25943974

13. Zhao Q, Zhou B, Ding D, Teramukai S, Guo Q, Fukushima M, et al. Cognitive decline in patients with Alzheimer's disease and its related factors in a memory clinic setting, Shanghai, China. PLoS One. 2014; 9, e95755. doi: 10.1371/journal.pone.0095755 24752600

14. Bloch F. A transient awakening of a patient with Alzheimer's disease that questions our practice. Clin Case Rep. 2016;4:376–378. doi: 10.1002/ccr3.530 27099731

15. Bloch K, Dar S, Vanichkin A, Gil-Ad I, Vardi P, Weizman A. Trafficking of grafted pancreatic islets into the brain lateral ventricles: implications for cognition. Transplantation. 2019;103:e137–e138. doi: 10.1097/TP.0000000000002671 30801525

16. Spector R, Robert Snodgrass S, Johanson CE. A balanced view of the cerebrospinal fluid composition and functions: Focus on adult humans. Exp Neurol. 2015;273:57–68. doi: 10.1016/j.expneurol.2015.07.027 26247808

17. Jäkel L, Van Nostrand WE, Nicoll JAR, Werring DJ, Verbeek MM. Animal models of cerebral amyloid angiopathy. Clin Sci (Lond). 2017 Sep 28;131:2469–2488.

18. Salkovic-Petrisic M, Osmanovic-Barilar J, Brückner MK, Hoyer S, Arendt T, Riederer P. Cerebral amyloid angiopathy in streptozotocin rat model of sporadic Alzheimer's disease: a long-term follow up study. J Neural Transm (Vienna). 2011;118:765–772.

19. Mao YF, Guo Z, Zheng T, Jiang Y, Yan Y, Yin X, et al. Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APPswe/PS1dE9 mice. Aging Cell. 2016; 15:893–902. doi: 10.1111/acel.12498 27457264

20. Chen Y, Zhao Y, Dai CL, Liang Z, Run X, Iqbal K, et al. Intranasal insulin restores insulin signaling, increases synaptic proteins, and reduces amyloid beta level and microglia activation in the brains of 3xTg-AD mice. Exp Neurol. 2014; 261:610–619. doi: 10.1016/j.expneurol.2014.06.004 24918340

21. Craft S, Claxton A, Baker LD, Hanson AJ, Cholerton B, Trittschuh EH, et al. Effects of Regular and Long-Acting Insulin on Cognition and Alzheimer's Disease Biomarkers: A Pilot Clinical Trial. J Alzheimers Dis. 2017;57:1325–1334. doi: 10.3233/JAD-161256 28372335

Článek vyšel v časopise


2020 Číslo 1
Nejčtenější tento týden