Disruption of cholinergic neurotransmission exacerbates Aβ-related cognitive impairment in preclinical Alzheimer's disease

Lim, Yen Ying; Maruff, Paul; Schindler, Rachel; Ott, Brian R.; Salloway, Stephen; Yoo, Don C.; Noto, Richard B.; Santos, Cláudia Y.; Snyder, Peter J.

doi:10.1016/j.neurobiolaging.2015.07.009

Cited by 61 publications

(50 citation statements)

References 31 publications

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“…Such correlation has also been observed in aged rodents (Fu et al, 2014; Lim et al, 2015). The first clinical approach has thus consisted in inhibiting the decrease of acetylcholine (ACh) by blocking its degradation by acetylcholinesterase (AChE) in the synaptic cleft (Marighetto et al, 2008).…”

Section: Introductionsupporting

confidence: 63%

The Synergistic Enhancing-Memory Effect of Donepezil and S 38093 (a Histamine H3 Antagonist) Is Mediated by Increased Neural Activity in the Septo-hippocampal Circuitry in Middle-Aged Mice

Sors

Krazem

Kehr³

et al. 2016

Front. Pharmacol.

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Donepezil, an acetylcholinesterase inhibitor, induces only moderate symptomatic effects on memory in Alzheimer’s disease patients. An alternative strategy for treatment of cognitive symptoms could be to act simultaneously on both histaminergic and cholinergic pathways, to create a synergistic effect. To that aim, 14 month old C57/Bl6 mice were administered per oesophagy during nine consecutive days with Donepezil (at 0.1 and 0.3 mg/kg) and S 38093 (at 0.1, 0.3, and 1.0 mg/kg), a H3 histaminergic antagonist developed by Servier, alone or in combination and tested for memory in a contextual memory task that modelized the age-induced memory dysfunction. The present study shows that the combination of Donepezil and S 38093 induced a dose-dependent synergistic memory-enhancing effect in middle-aged mice with a statistically higher size of effect never obtained with compounds alone and without any pharmacokinetic interaction between both compounds. We demonstrated that the memory-enhancing effect of the S 38093 and Donepezil combination is mediated by its action on the septo-hippocampal circuitry, since it canceled out the reduction of CREB phosphorylation (pCREB) observed in these brain areas in vehicle-treated middle-aged animals. Overall, the effects of drug combinations on pCREB in the hippocampus indicate that the synergistic promnesiant effects of the combination on memory performance in middle-aged mice stem primarily from an enhancement of neural activity in the septo-hippocampal system.

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Section: Introductionsupporting

confidence: 63%

The Synergistic Enhancing-Memory Effect of Donepezil and S 38093 (a Histamine H3 Antagonist) Is Mediated by Increased Neural Activity in the Septo-hippocampal Circuitry in Middle-Aged Mice

Sors

Krazem

Kehr³

et al. 2016

Front. Pharmacol.

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“…As a first step toward such applications, we demonstrated that the dissociated FC profiles of the identified CBF subdivisions are reproducible in rs‐fMRI acquisitions of elderly participants as typically collected in clinical research settings. We expect rs‐fMRI‐based assessments of CBF connectivity to be particularly useful for the study of functional CBF alterations in predementia stages of neurodegenerative disease (Brayda‐Bruno et al, ; Grothe, Ewers, Krause, Heinsen, & Teipel, ; Lim et al, ; Ray et al, ), as well as other neuropsychiatric conditions with cholinergic involvement that are not typically associated with gross neurodegeneration (Grothe et al, ; Perry et al, ; Sarter et al, ).…”

Section: Resultsmentioning

confidence: 99%

The corticotopic organization of the human basal forebrain as revealed by regionally selective functional connectivity profiles

Fritz

Ray

Dyrba

et al. 2018

Human Brain Mapping

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The cholinergic basal forebrain (CBF), comprising different groups of cortically projecting cholinergic neurons, plays a crucial role in higher cognitive processes and has been implicated in diverse neuropsychiatric disorders. A distinct corticotopic organization of CBF projections has been revealed in animal studies, but little is known about their organization in the human brain. We explored regional differences in functional connectivity (FC) profiles within the human CBF by applying a clustering approach to resting‐state functional magnetic resonance imaging (rs‐fMRI) data of healthy adult individuals (N = 85; 19–85 years). We further examined effects of age on FC of the identified CBF clusters and assessed the reproducibility of cluster‐specific FC profiles in independent data from healthy older individuals (N = 25; 65–89 years). Results showed that the human CBF is functionally organized into distinct anterior‐medial and posterior‐lateral subdivisions that largely follow anatomically defined boundaries of the medial septum/diagonal band and nucleus basalis Meynert. The anterior‐medial CBF subdivision was characterized by connectivity with the hippocampus and interconnected nodes of an extended medial cortical memory network, whereas the posterior‐lateral subdivision was specifically connected to anterior insula and dorsal anterior cingulate components of a salience/attention network. FC of both CBF subdivisions declined with increasing age, but the overall topography of subregion‐specific FC profiles was reproduced in independent rs‐fMRI data of healthy older individuals acquired in a typical clinical setting. Rs‐fMRI‐based assessments of subregion‐specific CBF function may complement established volumetric approaches for the in vivo study of CBF involvement in neuropsychiatric disorders.

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“…Second, the loss of cholinergic innervation of cerebral blood vessels in AD may also contribute to brain hypoperfusion. Indeed, disruptions in cholinergic neurotransmission are known to exacerbate cognitive impairments in pre-clinical AD (Lim et al, 2015). Compared to age-matched control subjects, AD patients exhibited greater blood brain barrier disruption (Erickson and Banks, 2013) and elevated expression of receptor for advanced glycation endproducts (RAGE) (Janota et al, 2016), which is essential for the influx of peripheral Aβ into the brain.…”

Section: Aging Of White Matter In Neurodegenerative Diseasesmentioning

confidence: 99%

Aging of cerebral white matter

Liu

Yang

Xia

et al. 2017

Ageing Research Reviews

197

136

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White matter (WM) occupies a large volume of the human cerebrum and is mainly composed of myelinated axons and myelin-producing glial cells. The myelinated axons within WM are the structural foundation for efficient neurotransmission between cortical and subcortical areas. Similar to neuron-enriched gray matter areas, WM undergoes a series of changes during the process of aging. WM malfunction can induce serious neurobehavioral and cognitive impairments. Thus, age-related changes in WM may contribute to the functional decline observed in the elderly. In addition, aged WM becomes more susceptible to neurological disorders, such as stroke, traumatic brain injury (TBI), and neurodegeneration. In this review, we summarize the structural and functional alterations of WM in natural aging and speculate on the underlying mechanisms. We also discuss how age-related WM changes influence the progression of various brain disorders, including ischemic and hemorrhagic stroke, TBI, Alzheimer’s disease, and Parkinson’s disease. Although the physiology of WM is still poorly understood relative to gray matter, WM is a rational therapeutic target for a number of neurological and psychiatric conditions.

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Disruption of cholinergic neurotransmission exacerbates Aβ-related cognitive impairment in preclinical Alzheimer's disease

Cited by 61 publications

References 31 publications

The Synergistic Enhancing-Memory Effect of Donepezil and S 38093 (a Histamine H3 Antagonist) Is Mediated by Increased Neural Activity in the Septo-hippocampal Circuitry in Middle-Aged Mice

The Synergistic Enhancing-Memory Effect of Donepezil and S 38093 (a Histamine H3 Antagonist) Is Mediated by Increased Neural Activity in the Septo-hippocampal Circuitry in Middle-Aged Mice

The corticotopic organization of the human basal forebrain as revealed by regionally selective functional connectivity profiles

Aging of cerebral white matter

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