Infliximab ameliorates AD-associated object recognition memory impairment

doi:10.1016/j.bbr.2016.06.001

Behavioural Brain Research

Volume 311, 15 September 2016, Pages 384-391

https://doi.org/10.1016/j.bbr.2016.06.001 Get rights and content

Highlights

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The administration of Aβ oligomers caused visual recognition memory impairment.
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Aβ oligomers perturbed mAChR-LTD in mouse PRh slices.
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Infliximab improved visual recognition memory impaired by pre-administered Aβ oligomers.
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Infliximab improved the detrimental Aβ effect on mAChR-LTD.

Abstract

Dysfunctions in the perirhinal cortex (PRh) are associated with visual recognition memory deficit, which is frequently detected in the early stage of Alzheimer’s disease. Muscarinic acetylcholine receptor–dependent long-term depression (mAChR-LTD) of synaptic transmission is known as a key pathway in eliciting this type of memory, and Tg2576 mice expressing enhanced levels of Aβ oligomers are found to have impaired mAChR-LTD in this brain area at as early as 3 months of age. We found that the administration of Aβ oligomers in young normal mice also induced visual recognition memory impairment and perturbed mAChR-LTD in mouse PRh slices. In addition, when mice were treated with infliximab, a monoclonal antibody against TNF-α, visual recognition memory impaired by pre-administered Aβ oligomers dramatically improved and the detrimental Aβ effect on mAChR-LTD was annulled. Taken together, these findings suggest that Aβ-induced inflammation is mediated through TNF-α signaling cascades, disturbing synaptic transmission in the PRh, and leading to visual recognition memory deficits.

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly [1], [2], [3]. AD is a progressive brain disorder, which initially affects the brain regions controlling memory and cognitive functions, spreading to adjacent regions involved in learning, communication, and behavior [4]. The major neuropathological hallmarks of AD are the extracellular amyloid neuritic plaques, intracellular neurofibrillary tangles, and neuronal degeneration [5]. Amyloid β peptide (Aβ) is the principal component of the extracellular amyloid neuritic plaques and interacts with the activated microglia [6] and reactive astrocytes surrounding these plaques [7], [8], [9]. A number of studies have demonstrated local increases in pro-inflammatory mediators in AD, which are generally assumed to exacerbate the progression of AD [10], [11], [12]. In multiple epidemiological studies, a significant reduction of AD risk has been observed in long-term as opposed to short-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) [13], [14].

Neuroinflammation plays a central role in the causation of AD by occurring in pathologically vulnerable regions of the brain and is more characteristic of chronic than acute inflammation, as it is not accompanied by swelling, heat, and pain [10], [15]. Given that inflammation in the central nervous system precedes neuronal damage in AD, the signs of chronic inflammation may serve as more sensitive markers for prodromal disease compared to the presence of neuritic plaques and neurofibrillary tangles. A growing body of evidence suggests that the three major pro-inflammatory cytokines, interleukin (IL)-1-β, IL-6, and tumor necrosis factor (TNF)-α, can mediate neurodegeneration and neuronal dysfunction. A general pattern of upregulation in the serum levels of these proinflammatory cytokines has been noticed in patients with AD [16], [17], especially with depression [18].

TNF-α, which can lead to apoptosis, has been implicated in the neurodegenerative changes associated with AD: increased levels occurred in the brains and plasma of patients with AD (Fillit et al.; Tarkowski), while the expression of TNF receptor type 1 (TNF-R1) was also increased (Li et al.). The activation of microglia by Aβ was demonstrated to result in the production of TNF-α (Chao et al.; Meda et al.). Moreover, TNF-α was identified as the principal neurotoxic agent resulting from Aβ-induced pro-inflammatory transcriptional changes (Combs et al.; Floden et al.). In addition, Aβ inhibition of long-term potentiation (LTP) of synaptic transmission in the mouse hippocampus was shown to be mediated via TNF-α [19].

Amyloid neuritic plaques and neurofibrillary tangles initially develop in the anterior subhippocampal area encompassing the perirhinal cortex (PRh) and entorhinal cortex before the hippocampal pathology begins [20], [21]. Lesions in this subhippocampal area are regarded as diagnostic signs for the preclinical and prodromal stage of AD, and the earliest diagnosis can be made at this time, which is critical for maximizing the efficacy of therapeutic interventions using disease-modifying agents, but the pathological changes are still minimal [22]. The PRh, located in the medial temporal area is involved in visual recognition memory [23], [24]. Mechanisms behind long-term depression (LTD) in the PRh, play a significant role in generating visual recognition memory [25], [26], [27], [28], [29] by reducing responsiveness following repetitive exposure to visual stimuli. This appears to involve various receptor types, including N-methyl-d-aspartate (NMDA) receptors, metabotropic glutamate receptors, and muscarinic acetylcholine receptors [25], [30]. The endocytosis of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors has also been reported to be a notable mediator of LTD in the PRh [28], [31]. There have not been many studies addressing whether Aβ oligomers disrupt LTD in the PRh leading to impaired visual recognition memory, but in a recent study, perturbed synaptic transmission and LTD were observed in the PRh of Tg2576 mice at 3 months of age, suggesting that Aβ has the potential to cause LTD impairment and related memory deficits in the PRh [32].

The present study demonstrated that infliximab, a Food and Drug Administration (FDA)-approved TNF-α antibody, ameliorated Aβ-induced muscarinic acetylcholine receptor-dependent LTD (mAChR-LTD) impairment in the PRh and related memory deficit, supporting a hypothesis that Aβ oligomers employ TNF-α-mediated inflammatory responses to elicit synaptic deficits in the PRh, thereby deteriorating visual recognition memory, an early symptom of AD.

Section snippets

Animals

Male ICR mice (25–30 g, 6 weeks old) were purchased from the Orient Co. Ltd., a branch of the Charles River Laboratories (Seoul, Korea). Mice were fed with food and water ad libitum and housed under a 12 h light/dark cycle (light on between 07:30–19:30 h) at 23 ± 1 °C with 60 ± 10% humidity. Animal treatment and maintenance were performed in accordance with the Principles of Laboratory Animal Care (NIH publication No. 85–23, revised 1985) and the Animal Care and Use Guidelines issued by Chonnam

Effect of infliximab on Aβ_1–42-induced object recognition memory impairment

To test the effect of infliximab on AD-like memory impairment, we first examined the effect of infliximab on Aβ_1–42-induced novel object recognition memory impairment. Mice treated with Aβ_1–42 (54 ng/6 μl, i.c.v.) [37] were subjected to behavioral test 24 h after. Infliximab (2 μg/6 μl, i.c.v.) [38] was injected with or without Aβ_1–42. Control mice showed significantly more exploration time to novel object compared to familiar object (t₁₄ = 4.876, P = 0.0002, n = 8/group, Fig. 1A). In contrast, Aβ_1–42

Discussion

Present data demonstrate that treatment of mice with infliximab, a monoclonal antibody against TNF-α, results in dramatic improvement in visual recognition memory which had been compromised by pre-administration of pathogenic Aβ oligomers. Impairment in mAChR-LTD by Aβ treatment in the mouse PRh slices, involved in visual recognition memory, was also rescued by infliximab treatment, indicating that cholinergic transmission underlying visual recognition memory is one of the target functions of

Acknowledgment

This work was supported by a grant from the Brain Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning NRF-2014M3C7A1046041 (to Kim BC).

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¹: These authors contributed equally to this work.

²: Current address: Life Science Research Institute, Daewoong Pharmaceutical Co., Ltd., Gyeonggi-Do, Republic of Korea.

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Research reportInfliximab ameliorates AD-associated object recognition memory impairment

Highlights

Abstract

Introduction

Section snippets

Animals

Effect of infliximab on Aβ1–42-induced object recognition memory impairment

Discussion

Acknowledgment

Neurobiol. Aging

Neurobiol. Aging

Biol. Psychiatry

Neuron

Neuron

Neurobiol. Aging

Neuron

Neuron

Neuron

Am. J. Pathol.

Behav. Brain Res.

Neuropsychologia

[The epidemiology of dementia and Alzheimer disease in Portugal: estimations of prevalence and treatment-costs]

Acta Med. Port.

2015 Alzheimer's disease facts and figures

Alzheimers Dement.

Emerging therapeutics for Alzheimer's disease

Annu. Rev. Pharmacol. Toxicol.

Emerging concepts in Alzheimer's disease

Annu. Rev. Pathol.

Alzheimer's disease

N. Engl. J. Med.

The role of microglia in amyloid clearance from the AD brain

J. Neural Transm.

Adult mouse astrocytes degrade amyloid-beta in vitro and in situ

Nat. Med.

Astrocytes: biology and pathology

Acta Neuropathol.

Astroglia in dementia and Alzheimer's disease

Cell Death Differ.

Toll-like receptors in Alzheimer's disease

Curr. Top. Microbiol. Immunol.

A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity

Nature

Do nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer's disease? The Rotterdam Study

Neurology

Clinical aspects of inflammation in Alzheimer's disease

Int. Rev. Psychiatry

Cerebrospinal fluid and blood biomarkers in Alzheimer's disease

World J. Psychiatry.

Raised serum proinflammatory cytokines in Alzheimer's disease with depression

Aging Dis.

Anwyl R. Beta-amyloid inhibition of long-term potentiation is mediated via tumor necrosis factor

Eur. J. Neurosci.

Neuropathological stageing of Alzheimer-related changes

Acta Neuropathol.

Neuropathological alterations in Alzheimer disease

Cold Spring Harb. Perspect. Med.

Developing new treatments for Alzheimer's disease: the who, what, when, and how of biomarker-guided therapies

Int. Psychogeriatr.

Research report
Infliximab ameliorates AD-associated object recognition memory impairment

Effect of infliximab on Aβ_1–42-induced object recognition memory impairment