Aβ oligomer induced cognitive impairment and evaluation of ACU193‐MNS‐based MRI in rabbit

Rozema, Nicholas B.; Procissi, Daniele; Bertolino, Nicola; Viola, Kirsten L.; Nandwana, Vikas; Abdul, Nafay; Pribus, Sophia; Dravid, Vinayak P.; Klein, William L.; Disterhoft, John F.; Weiss, Craig

doi:10.1002/trc2.12087

Cited by 7 publications

(8 citation statements)

References 53 publications

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“…According to a recent study, AβOs injections resulted in signi cant impairment of the object location memory index. In this study, AβOs impair performance in hippocampal-dependent associative learning tasks [49]. Also, AβOs injection resulted in signi cant impairment of the spatial memory index score for the object location memory test [50].…”

Section: Discussionsupporting

confidence: 47%

Investigation of Cyclo-Z Therapeutic Effect on Insulin Pathway in Alzheimer's Rat Model: Biochemical and Electrophysiological Parameters

Acun

Kantar

et al. 2023

Mol Neurobiol

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BackgroundCyclo (his-pro-CHP) plus zinc (Zn + 2 ) (Cyclo-Z) is the only chemical agent known to stimulate IDE synthesis and reduction of inactive cellular insulin fragments. ObjectivesThe aim of this study was to characterize the effects of Cyclo-Z on insulin pathway, memory functions and brain oscillations in the Alzheimer's disease (AD) rat model. MethodsThe rat model of AD was established by bilateral injection of Aβ42 oligomer (2,5nmol/10µl) into the lateral ventricles. Cyclo-Z (10mg Zn + 2 /kg and 0,2mg CHP/kg, daily) was administered orally by gavage for 21 days. At the end of the experimental period, memory tests and electrophysiological recordings were performed which followed by the biochemical analysis. ResultsAβ42 oligomers led to a signi cant increase in fasting blood glucose, serum insülin, Homeostatic Model Assessment for Insulin Resistance(HOMA-IR) and phospho-tau-Ser356 levels. Moreover, Aβ42 oligomers caused a signi cant decrement in body weight, hippocampal insulin, brain insulin receptor substrate(IRS-Ser612), and glycogen synthase kinase-3 beta(GSK-3β) levels. Also, Aβ42 oligomers resulted in a signi cant reduction in memory. The Cyclo-Z treatment prevented the observed alterations in the ADZ group except for phospho-tau levels and attenuated the increased Aβ42 oligomers levels in the ADZ group. We also found that the Aβ42 oligomer decreased the left temporal spindle and delta power during ketamine anesthesia. Cyclo-Z treatment reversed the Aβ42 oligomer-related alterations in the left temporal spindle power. ConclusionsCyclo-Z prevents Aβ oligomer-induced changes in the insulin pathway, amyloid toxicity, and may contribute to the improvement of memory de cits and neural network dynamics in this rat model.

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Section: Discussionsupporting

confidence: 47%

Investigation of Cyclo-Z Therapeutic Effect on Insulin Pathway in Alzheimer's Rat Model: Biochemical and Electrophysiological Parameters

Acun

Kantar

et al. 2023

Mol Neurobiol

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“…In addition, our model can be used effectively for comprehensive therapeutic testing of novel treatments through the use of behavioral tests (i.e., the temporal association trace EBC assay and the object location test), and through MRI detection of iron oxide labeled agents that target amyloid oligomers (an early biomarker for AD) as reported for rabbits injected with synthetic amyloid oligomers. 50…”

Section: Discussionmentioning

confidence: 99%

“…Combining the rabbit model with additional transgenic models has the potential to provide a comprehensive set of tools for multi‐scale characterization of molecular mechanisms underlying AD pathophysiology and the effects of potential therapeutics on progression of the disease. In addition, our model can be used effectively for comprehensive therapeutic testing of novel treatments through the use of behavioral tests (i.e., the temporal association trace EBC assay and the object location test), and through MRI detection of iron oxide labeled agents that target amyloid oligomers (an early biomarker for AD) as reported for rabbits injected with synthetic amyloid oligomers 50 …”

Section: Discussionmentioning

confidence: 99%

Diet‐induced Alzheimer's‐like syndrome in the rabbit

Weiss

Bertolino

Procissi

et al. 2022

A&D Transl Res & Clin Interv

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Introduction:Although mouse models of Alzheimer's disease (AD) have increased our understanding of the molecular basis of the disease, none of those models represent late-onset Alzheimer's Disease which accounts for >90% of AD cases, and no therapeutics developed in the mouse (with the possible exceptions of aduhelm/aducanumab and gantenerumab) have succeeded in preventing or reversing the disease. This technology has allowed much progress in understanding the molecular basis of AD. To further enhance our understanding, we used wild-type rabbit (with a nearly identical amino acid sequence for amyloid as in humans) to model LOAD by stressing risk factors including age, hypercholesterolemia, and elevated blood glucose levels (BGLs), upon an ε3-like isoform of apolipoprotein. We report a combined behavioral, imaging, and metabolic study using rabbit as a non-transgenic model to examine effects of AD-related risk factors on cognition, intrinsic functional connectivity, and magnetic resonance-based biomarkers of neuropathology.Methods: Aging rabbits were fed a diet enriched with either 2% cholesterol or 10% fat/30% fructose. Monthly tests of novel object recognition (NOR) and object location memory (OLM) were administered to track cognitive impairment. Trace eyeblink conditioning (EBC) was administered as a final test of cognitive impairment. Magnetic resonance imaging (MRI) was used to obtain resting state connectivity and quantitative parametric data (R 2 *).Results: Experimental diets induced hypercholesterolemia or elevated BGL. Both experimental diets induced statistically significant impairment of OLM (but not NOR) and altered intrinsic functional connectivity. EBC was more impaired by fat/fructose diet than by cholesterol. Whole brain and regional R 2 * MRI values were elevated in both experimental diet groups relative to rabbits on the control diet.Discussion: We propose that mechanisms underlying LOAD can be assessed by stressing risk factors for inducing AD and that dietary manipulations can be used to assess etiological differences in the pathologies and effectiveness of potential therapeuticsThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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“…Viola et al reported using 12–16 nm Fe 3 O 4 magnetic nanostructures (MNS) conjugated with Aβ-oligomer-specific antibody NU4 for detecting Aβ oligomers in mouse brains [ 53 ]. Rozema et al reported Aβ-oligomer-specific antibody-based ACU193-MNS for detecting the Aβ oligomer levels in rabbits by using MRI [ 54 ]. As the size of the antibody hinders the permeability of its blood–brain barrier (BBB), one strategy to facilitate the antibody delivery is to link a fraction of the antibody with a transferrin [ 55 ] or scavenger receptor.…”

Section: Aβ Imagingmentioning

confidence: 99%

Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

2021

IJMS

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Amyloid-beta (Aβ) plays an important role in the pathogenesis of Alzheimer’s disease. Aberrant Aβ accumulation induces neuroinflammation, cerebrovascular alterations, and synaptic deficits, leading to cognitive impairment. Animal models recapitulating the Aβ pathology, such as transgenic, knock-in mouse and rat models, have facilitated the understanding of disease mechanisms and the development of therapeutics targeting Aβ. There is a rapid advance in high-field MRI in small animals. Versatile high-field magnetic resonance imaging (MRI) sequences, such as diffusion tensor imaging, arterial spin labeling, resting-state functional MRI, anatomical MRI, and MR spectroscopy, as well as contrast agents, have been developed for preclinical imaging in animal models. These tools have enabled high-resolution in vivo structural, functional, and molecular readouts with a whole-brain field of view. MRI has been used to visualize non-invasively the Aβ deposits, synaptic deficits, regional brain atrophy, impairment in white matter integrity, functional connectivity, and cerebrovascular and glymphatic system in animal models of Alzheimer’s disease amyloidosis. Many of the readouts are translational toward clinical MRI applications in patients with Alzheimer’s disease. In this review, we summarize the recent advances in MRI for visualizing the pathophysiology in amyloidosis animal models. We discuss the outstanding challenges in brain imaging using MRI in small animals and propose future outlook in visualizing Aβ-related alterations in the brains of animal models.

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Aβ oligomer induced cognitive impairment and evaluation of ACU193‐MNS‐based MRI in rabbit

Cited by 7 publications

References 53 publications

Investigation of Cyclo-Z Therapeutic Effect on Insulin Pathway in Alzheimer's Rat Model: Biochemical and Electrophysiological Parameters

Investigation of Cyclo-Z Therapeutic Effect on Insulin Pathway in Alzheimer's Rat Model: Biochemical and Electrophysiological Parameters

Diet‐induced Alzheimer's‐like syndrome in the rabbit

Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

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