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

ABSTRACT: 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-? 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-? 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.

SUBMITTER: Bloch K

PROVIDER: S-EPMC6957181 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Bloch Konstantin K Hornfeld Shay Henry SH Dar Shira S Vanichkin Alexey A Gil-Ad Irit I Vardi Pnina P Weizman Abraham A

PloS one 20200113 1

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 ...[more]

PMID: 31929603

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Project description:Alzheimer's disease (AD) is characterized by multiple cognitive deficits including memory and sensorimotor gating impairments as a result of neuronal and synaptic loss. The endocannabinoid system plays an important role in these deficits but little is known about its influence on the molecular mechanism regarding phosphorylated tau (p-tau) protein accumulation - one of the hallmarks of AD -, and on the density of synaptic proteins. Thus, the aim of this study was to investigate the preventive effects of anandamide (N-arachidonoylethanolamine, AEA) on multiple cognitive deficits and on the levels of synaptic proteins (syntaxin 1, synaptophysin and synaptosomal-associated protein, SNAP-25), cannabinoid receptor type 1 (CB1) and molecules related to p-tau degradation machinery (heat shock protein 70, HSP70), and Bcl2-associated athanogene (BAG2) in an AD-like sporadic dementia model in rats using intracerebroventricular (icv) injection of streptozotocin (STZ). Our hypothesis is that AEA could interact with HSP70, modulating the level of p-tau and synaptic proteins, preventing STZ-induced cognitive impairments. Thirty days after receiving bilateral icv injections of AEA or STZ or both, the cognitive performance of adult male Wistar rats was evaluated in the object recognition test, by the escape latency in the elevated plus maze (EPM), by the tone and context fear conditioning as well as in prepulse inhibition tests. Subsequently, the animals were euthanized and their brains were removed for histological analysis or for protein quantification by Western Blotting. The behavioral results showed that STZ impaired recognition, plus maze and tone fear memories but did not affect contextual fear memory and prepulse inhibition. Moreover, AEA prevented recognition and non-associative emotional memory impairments induced by STZ, but did not influence tone fear conditioning. STZ increased the brain ventricular area and this enlargement was prevented by AEA. Additionally, STZ reduced the levels of p-tau (Ser199/202) and increased p-tau (Ser396), although AEA did not affect these alterations. HSP70 was found diminished only by STZ, while BAG2 levels were decreased by STZ and AEA. Synaptophysin, syntaxin and CB1 receptor levels were reduced by STZ, but only syntaxin was recovered by AEA. Altogether, albeit AEA failed to modify some AD-like neurochemical alterations, it partially prevented STZ-induced cognitive impairments, changes in synaptic markers and ventricle enlargement. This study showed, for the first time, that the administration of an endocannabinoid can prevent AD-like effects induced by STZ, boosting further investigations about the modulation of endocannabinoid levels as a therapeutic approach for AD.

Dataset Information

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

Publications

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

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