Cholinergic dysfunction in a mouse model of Alzheimer’s disease is reversed by an anti-ABeta antibody

Neuroscience Discovery Research, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 04/2006; 116(3):825-32. DOI: 10.1172/JCI27120
Source: PubMed


Disruption of cholinergic neurotransmission contributes to the memory impairment that characterizes Alzheimer disease (AD). Since the amyloid cascade hypothesis of AD pathogenesis postulates that amyloid beta (A beta) peptide accumulation in critical brain regions also contributes to memory impairment, we assessed cholinergic function in transgenic mice where the human A beta peptide is overexpressed. We first measured hippocampal acetylcholine (ACh) release in young, freely moving PDAPP mice, a well-characterized transgenic mouse model of AD, and found marked A beta-dependent alterations in both basal and evoked ACh release compared with WT controls. We also found that A beta could directly interact with the high-affinity choline transporter which may impair steady-state and on-demand ACh release. Treatment of PDAPP mice with the anti-A beta antibody m266 rapidly and completely restored hippocampal ACh release and high-affinity choline uptake while greatly reducing impaired habituation learning that is characteristic of these mice. Thus, soluble "cholinotoxic" species of the A beta peptide can directly impair cholinergic neurotransmission in PDAPP mice leading to memory impairment in the absence of overt neurodegeneration. Treatment with certain anti-A beta antibodies may therefore rapidly reverse this cholinergic dysfunction and relieve memory deficits associated with early AD.

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Available from: Steven M Paul, Oct 03, 2015
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    • "Progressively, alterations of cholinergic neurotransmission, depletion in ACh, decrease in AChE activity and loss of cholinergic neurons are observed in AD patient brains and transgenic AD mouse models [12] [13] [14] [15] [16]. The degeneration of cholinergic systems is directly responsible for the progressive impairments in memory and cognitive function [15] [16]. Interestingly, BChE activity is unchanged or increased in several brain regions in AD patient brains [14,17–19]. "
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    ABSTRACT: Butyrylcholinesterase (BChE) is an important enzyme for detoxication and metabolism of ester compounds. It also hydrolyzes the neurotransmitter acetylcholine (ACh) in pathological conditions and may play a role in Alzheimer's disease (AD). We here compared the learning ability and vulnerability to Aβ toxicity in male and female BChE knockout (KO) mice and their 129Sv wild-type (Wt) controls. Animals tested for place learning in the water-maze showed increased acquisition slopes and presence in the training quadrant during the probe test. An increased passive avoidance response was also observed for males. BChE KO mice therefore showed enhanced learning ability in spatial and non-spatial memory tests. Intracerebroventricular (ICV) injection of increasing doses of amyloid-β[25-35] (Aβ25-35) peptide oligomers resulted, in Wt mice, in learning and memory deficits, oxidative stress and decrease in ACh hippocampal content. In BChE KO mice, the Aβ25-35-induced deficit in place learning was attenuated in males and blocked in females. No change in lipid peroxidation or ACh levels was observed after Aβ25-35 treatment in male or female BChE KO mice. These data showed that the genetic invalidation of BChE in mice augmented learning capacities and lowered the vulnerability to Aβ toxicity. Copyright © 2015. Published by Elsevier B.V.
    Behavioural brain research 08/2015; DOI:10.1016/j.bbr.2015.08.026 · 3.03 Impact Factor
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    • "Transplantation of stem cells has shown promise for improving functional recovery for Alzheimer's disease. MSCs could promote survival, increased the metabolic activity and help to rescue the AD cell model in vitro [47]. The coculture of human MSCs and BV-2, mouse microglia, increased neprilysine expression, the Aβ-degrading enzyme, under the exposure of Aβ [48]. "
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    ABSTRACT: The loss of neuronal cells in the central nervous system may occur in many neurodegenerative diseases. Alzheimer's disease is a common senile disease in people over 65 years, and it causes impairment characterized by the decline of mental function, including memory loss and cognitive impairment, and affects the quality of life of patients. However, the current therapeutic strategies against AD are only to relieve symptoms, but not to cure it. Because there are only a few therapeutic strategies against Alzheimer's disease, we need to understand the pathogenesis of this disease. Cell therapy may be a powerful tool for the treatment of Alzheimer's disease. This review will discuss the characteristics of Alzheimer's disease and various available therapeutic strategies.
    03/2014; 23(1):45-52. DOI:10.5607/en.2014.23.1.45
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    • "For instance, in the brain of 8 months old transgenic Tg2576 mice, when there is no accumulation of Ab yet, reduced binding levels of cortical and hippocampal M1 mAChR were observed [44]. Recent data shows as well that the reduced hippocampal release of ACh was due to a significant increase in the rate of high affinity choline uptake, suggesting a possible compensatory mechanism in response to an impairment of the cholinergic synapses [45] [46]. "
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    ABSTRACT: Although widely explored, the pathogenesis of Alzheimer's disease (AD) has yet to be cleared. Over the past twenty years the so call amyloid cascade hypothesis represented the main research paradigm in AD pathogenesis. In spite of its large consensus, the proposed role of β-amyloid (Aβ) remain to be elucidated. Many evidences are starting to cast doubt on Aβ as the primary causative factor in AD. For instance, Aβ is deposited in the brain following many different kinds of injury. Also, concentration of Aβ needed to induce toxicity in vitro are never reached in vivo. In this review we propose an amyloid-independent interpretation of several AD pathogenic features, such as synaptic plasticity, endo-lysosomal trafficking, cell cycle regulation and neuronal survival.
    FEBS letters 01/2014; 588(5). DOI:10.1016/j.febslet.2013.12.038 · 3.17 Impact Factor
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