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Selective loss of noradrenaline exacerbates early cognitive dysfunction and synaptic deficits in APP/PS1 mice.

ABSTRACT: Degeneration of the locus coeruleus (LC), the major noradrenergic nucleus in the brain, occurs early and is ubiquitous in Alzheimer's disease (AD). Experimental lesions to the LC exacerbate AD-like neuropathology and cognitive deficits in several transgenic mouse models of AD. Because the LC contains multiple neuromodulators known to affect amyloid ? toxicity and cognitive function, the specific role of noradrenaline (NA) in AD is not well understood.To determine the consequences of selective NA deficiency in an AD mouse model, we crossed dopamine ?-hydroxylase (DBH) knockout mice with amyloid precursor protein (APP)/presenilin-1 (PS1) mice overexpressing mutant APP and PS1. Dopamine ?-hydroxylase (-/-) mice are unable to synthesize NA but otherwise have normal LC neurons and co-transmitters. Spatial memory, hippocampal long-term potentiation, and synaptic protein levels were assessed.The modest impairments in spatial memory and hippocampal long-term potentiation displayed by young APP/PS1 or DBH (-/-) single mutant mice were augmented in DBH (-/-)/APP/PS1 double mutant mice. Deficits were associated with reduced levels of total calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptor 2A and increased N-methyl-D-aspartate receptor 2B levels and were independent of amyloid ? accumulation. Spatial memory performance was partly improved by treatment with the NA precursor drug L-threo-dihydroxyphenylserine.These results indicate that early LC degeneration and subsequent NA deficiency in AD may contribute to cognitive deficits via altered levels of calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptors and suggest that NA supplementation could be beneficial in early AD.

SUBMITTER: Hammerschmidt T

PROVIDER: S-EPMC4712953 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Selective loss of noradrenaline exacerbates early cognitive dysfunction and synaptic deficits in APP/PS1 mice.

Hammerschmidt Thea T Kummer Markus P MP Terwel Dick D Martinez Ana A Gorji Ali A Pape Hans-Christian HC Rommelfanger Karen S KS Schroeder Jason P JP Stoll Monika M Schultze Joachim J Weinshenker David D Heneka Michael T MT

Biological psychiatry 20120809 5

<h4>Background</h4>Degeneration of the locus coeruleus (LC), the major noradrenergic nucleus in the brain, occurs early and is ubiquitous in Alzheimer's disease (AD). Experimental lesions to the LC exacerbate AD-like neuropathology and cognitive deficits in several transgenic mouse models of AD. Because the LC contains multiple neuromodulators known to affect amyloid β toxicity and cognitive function, the specific role of noradrenaline (NA) in AD is not well understood.<h4>Methods</h4>To determi ...[more]

PMID: 22883210

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Project description:Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by a progressive cognitive decline. Epidemiological studies have suggested a protective role of caffeine consumption against age-related cognitive impairments and the risk of developing AD. Effects of caffeine have been particularly ascribed to its ability to block adenosine A2A receptors (A2ARs). Early pathological upregulation of these receptors by neurons is thought to be involved in the development of synaptic and memory deficits in AD but this remains ill-defined. To tackle this question, we employed a novel transgenic mouse model allowing to promote a neuronal upregulation of A2AR in the hippocampus of APP/PS1 mice, developing AD-like amyloidogenesis. This new model was used to determine the impact of an early upregulation of A2AR on the progression of neuropathological lesions, associated behavior and underlying mechanisms in APP/PS1 mice. Our findings revealed that the early upregulation of A2AR in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioral changes were not linked to major change in the development of amyloid pathology but rather associate with an increased p-tau at neuritic plaques. Moreover, proteomic and transcriptomic analysis coupled to quantitative immunofluorescence studies indicated that neuronal impairment of the receptor promoted both neuronal- and non-neuronal autonomous alterations i.e. loss of excitatory synapses and neuroinflammatory response, respectively, both presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A2AR dysfunction as seen in the brain of patients contributes to AD pathogenesis, favoring synaptic deficits promoted by both amyloid (this study) and tau lesions (our previous study). In addition to provide new insights into the complex pathophysiology of AD, the present findings underscore the potential of A2AR as a relevant therapeutic target for mitigating early synaptic loss in this neurodegenerative disorder.

Project description:BackgroundAmyloid beta (Aβ) which is recognized as a main feature of Alzheimer's disease (AD) has been proposed to "spread" through anatomically and functionally connected brain regions. The entorhinal cortex and perforant path are the earliest affected brain regions in AD. The perforant path is the most vulnerable circuit in the cortex with respect to both aging and AD. Previous data show that the origins and terminations of the perforant path are susceptible to amyloid deposition at the younger age in AD. Nogo receptor (NgR) plays an essential role in limiting injury-induced axonal growth and experience-dependent plasticity in the adult brain. It has been suggested that NgR is involved in AD pathological features, but the results have been conflicting and the detailed mechanism needs further investigation. In this study, the effect of NgR in the perforant path on the pathological and functional phenotype of APP/PS1 transgenic mice was studied.MethodsTo genetically manipulate NgR expression, adeno-associated virus (AAV) with short hairpin (shRNA) against NgR was injected into the perforant path of APP/PS1 transgenic mice, followed by an assessment of behavioral, synaptic plasticity and neuropathological phenotypes. NgR was overexpressed or knockdown in neuroblastoma N2a cells and APPswe/HEK293 cells to investigate the interaction between NgR and amyloid precursor protein (APP).ResultsIt is shown that reduction of NgR in the perforant path rescued cognitive and synaptic deficits in APP/PS1 transgenic mice. Concurrently, Aβ production in the perforant path and levels of soluble Aβ and amyloid plaques in the hippocampus were significantly decreased. There was a positive correlation between the total APP protein level and NgR expression both in transgenic mice and in cultured cells, where the α-secretase and β-secretase cleavage products both changed with APP level in parallel. Finally, NgR might inhibit APP degradation through lysosome by Rho/Rho-associated protein kinases (ROCK) signaling pathway.ConclusionsOur findings demonstrate that perforant path NgR plays an important role in regulating APP/Aβ level and cognitive functions in AD transgenic mice, which might be related to the suppression of APP degradation by NgR. Our study suggests that NgR in the perforant path could be a potential target for modulating AD progression.

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Selective loss of noradrenaline exacerbates early cognitive dysfunction and synaptic deficits in APP/PS1 mice.

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Selective loss of noradrenaline exacerbates early cognitive dysfunction and synaptic deficits in APP/PS1 mice.

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