Selective cholinergic denervation, independent from oxidative stress, in a mouse model of Alzheimer’s disease

Aucoin, Jean-Sebastien; Jiang, P.; Aznavour, Nicolas; Tong, Xin‐Kang; Buttini, Manuel; Descarries, Laurent; Hamel, Edith

doi:10.1016/j.neuroscience.2004.11.047

Cited by 60 publications

(42 citation statements)

References 78 publications

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“…Thus, behavioral changes reported in this article take place without any changes to the major cholinergic markers. In addition, at the age that APP mice were tested in this study, they do not present detectable cholinergic deficits despite signs of cognitive deficits (Aucoin et al, 2005), so we did not anticipate detectable changes to cholinergic markers. Perhaps at later stages or older age, there may be a change to cholinergic markers.…”

Section: Discussionmentioning

confidence: 91%

Ligand-Dependent TrkA Activity in Brain Differentially Affects Spatial Learning and Long-Term Memory

Aboulkassim

Tong²,

Tse³

et al. 2011

Mol Pharmacol

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In the central nervous system, the nerve growth factor (NGF) receptor TrkA is expressed primarily in cholinergic neurons that are implicated in spatial learning and memory, whereas the NGF receptor p75NTR is expressed in many neuronal populations and glia. We asked whether selective TrkA activation may have a different impact on learning, short-term memory, and long-term memory. We also asked whether TrkA activation might affect cognition differently in wild-type mice versus mice with cognitive deficits due to transgenic overexpression of mutant amyloid-precursor protein (APP mice). Mice were treated with wild-type NGF (a ligand of TrkA and p75 NTR ) or with selective pharmacological agonists of TrkA that do not bind to p75NTR . In APP mice, the selective TrkA agonists significantly improved learning and short-term memory. These improvements are associated with a reduction of soluble A␤ levels in the cortex and AKT activation in the cortex and hippocampus. However, this improved phenotype did not translate into improved long-term memory. In normal wild-type mice, none of the treatments affected learning or short-term memory, but a TrkA-selective agonist caused persistent deficits in long-term memory. The deficit in wild-type mice was associated temporally, in the hippocampus, with increased AKT activity, increased brain-derived neurotrophic factor precursor, increased neurotrophin receptor homolog-2 (p75-related protein), and long-term depression. Together, these data indicate that selective TrkA activation affects cognition but does so differently in impaired APP mice versus normal wild-type mice. Understanding mechanisms that govern learning and memory is important for better treatment of cognitive disorders.

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Section: Discussionmentioning

confidence: 91%

Ligand-Dependent TrkA Activity in Brain Differentially Affects Spatial Learning and Long-Term Memory

Aboulkassim

Tong²,

Tse³

et al. 2011

Mol Pharmacol

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“…55 It seems unrelated to A␤ deposition, since no relationship could be established between the presence and location of A␤ plaques and denervation severity. 25 However, despite the increase in soluble A␤ oligomers from adult to old A/T mice, the cholinergic denervation did not gain in severity with aging. This stabilization could result from a TGF-␤1 protective effect on neurons.…”

Section: Contribution Of A␤ Versus Tgf-␤1 To the Neuronal And Cognitimentioning

confidence: 93%

“…ChAT immunostaining was tested only in adult and old A/T mice when cholinergic innervation is preserved in TGF mice, 24 but significantly reduced in singly transgenic APP mice. 23,25 Freefloating thick sections were stained with 1% Thioflavin S (8 minutes) to reveal mature, dense core amyloid plaques or incubated with rabbit anti-GFAP (1:1000; DAKO, Mississauga, ON, Canada), followed by donkey anti-rabbit cyanin 2 (Cy2)-conjugated secondary antibody (1:400; Jackson ImmunoResearch) for the detection of activated astrocytes. Sections were observed under light microscopy or epifluorescence (Leitz Aristoplan microscope, Leica, Montréal, QC), and digital pictures acquired (Coolpix 4500; Nikon, Tokyo, Japan).…”

Section: Histochemistry and Immunohistochemistrymentioning

confidence: 99%

“…23,25,28 Namely, the loss of cortical ChAT-positive fibers, a landmark of AD 51 reproduced in APP mouse models 25,[52][53][54] but not in TGF mice, 24 has been attributed to the cholinotoxic effects of soluble A␤. 55 It seems unrelated to A␤ deposition, since no relationship could be established between the presence and location of A␤ plaques and denervation severity.…”

Section: Contribution Of A␤ Versus Tgf-␤1 To the Neuronal And Cognitimentioning

confidence: 99%

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Transgenic Mice Overexpressing APP and Transforming Growth Factor-β1 Feature Cognitive and Vascular Hallmarks of Alzheimer's Disease

Ongali

Nicolakakis

Lecrux

et al. 2010

The American Journal of Pathology

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High brain levels of amyloid-␤ (A␤) and transforming growth factor-␤1 (TGF-␤1) have been implicated in the cognitive and cerebrovascular alterations of Alzheimer's disease (AD). We sought to investigate the impact of combined increases in A␤ and TGF-␤1 on cerebrovascular, neuronal, and mnemonic function using transgenic mice overproducing these peptides (A/T mice). In particular, we measured cerebrovascular reactivity, evoked cerebral blood flow and glucose uptake during brain activation, cholinergic status, and spatial memory, along with cerebrovascular fibrosis, amyloidosis, and astrogliosis, and their evolution with age. An assessment of perfusion and metabolic responses was considered timely, given ongoing efforts for their validation as AD biomarkers. Relative to wild-type littermates, A/T mice displayed an early progressive decline in cerebrovascular dilatory ability, preserved contractility, and reduction in constitutive nitric oxide synthesis that establishes resting vessel tone. Altered levels of vasodilator-synthesizing enzymes and fibrotic proteins, resistance to antioxidant treatment, and unchanged levels of the antioxidant enzyme, superoxide dismutase-2, accompanied these impairments. A/T mice featured deficient neurovascular and neurometabolic coupling to whisker stimulation, cholinergic denervation, cerebral and cerebrovascular A␤ deposition, astrocyte activation , and impaired Morris water maze performance , which gained severity with age. The combined A␤-and TGF-␤1-driven pathology recapitulates salient cerebrovascular, neuronal, and cognitive AD landmarks and yields a versatile model toward highly anticipated diagnostic and therapeutic tools for patients featuring A␤ and TGF-␤1 increments.

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“…Sod2 is enriched around amyloid plaques (Blanchard et al, 2003;Aucoin et al, 2005) and brain microvessels in hAPP transgenic mice but decreased in AD brains overall (Omar et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Reduction in Mitochondrial Superoxide Dismutase Modulates Alzheimer's Disease-Like Pathology and Accelerates the Onset of Behavioral Changes in Human Amyloid Precursor Protein Transgenic Mice

Esposito¹,

Raber²,

Kekonius³

et al. 2006

J. Neurosci.

233

166

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Alzheimer's disease (AD) is associated with accumulations of amyloid-␤ (A␤) peptides, oxidative damage, mitochondrial dysfunction, neurodegeneration, and dementia. The mitochondrial antioxidant manganese superoxide dismutase-2 (Sod2) might protect against these alterations. To test this hypothesis, we inactivated one Sod2 allele (Sod2 ϩ/Ϫ ) in human amyloid precursor protein (hAPP) transgenic mice, reducing Sod2 activity to ϳ50% of that in Sod2 wild-type (Sod2 ϩ/ϩ ) mice. A reduction in Sod2 activity did not obviously impair mice without hAPP/A␤ expression. In hAPP mice, however, it accelerated the onset of behavioral alterations and of deficits in prepulse inhibition of acoustic startle, a measure of sensorimotor gating. In these mice, it also worsened hAPP/A␤-dependent depletion of microtubule-associated protein 2, a marker of neuronal dendrites. Sod2 reduction decreased amyloid plaques in the brain parenchyma but promoted the development of cerebrovascular amyloidosis, gliosis, and plaque-independent neuritic dystrophy. Sod2 reduction also increased the DNA binding activity of the transcription factor nuclear factor B. These results suggest that Sod2 protects the aging brain against hAPP/A␤-induced impairments. Whereas reductions in Sod2 would be expected to trigger or exacerbate neuronal and vascular pathology in AD, increasing Sod2 activity might be of therapeutic benefit.

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Selective cholinergic denervation, independent from oxidative stress, in a mouse model of Alzheimer’s disease

Cited by 60 publications

References 78 publications

Ligand-Dependent TrkA Activity in Brain Differentially Affects Spatial Learning and Long-Term Memory

Ligand-Dependent TrkA Activity in Brain Differentially Affects Spatial Learning and Long-Term Memory

Transgenic Mice Overexpressing APP and Transforming Growth Factor-β1 Feature Cognitive and Vascular Hallmarks of Alzheimer's Disease

Reduction in Mitochondrial Superoxide Dismutase Modulates Alzheimer's Disease-Like Pathology and Accelerates the Onset of Behavioral Changes in Human Amyloid Precursor Protein Transgenic Mice

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