Abstract
To successfully treat Alzheimer's disease (AD), pathophysiological events in preclinical stages need to be identified. Preclinical AD refers to the stages that exhibit amyloid deposition in the brain but have normal cognitive function, which are replicated in young adult APPswe/PS1deltaE9 (deltaE9) mice. By long-term in vivo two-photon microscopy, we demonstrate impaired adaptive spine plasticity in these transgenic mice illustrated by their failure to increase dendritic spine density and form novel neural connections when housed in enriched environment (EE). Decrease of amyloid plaques by reducing BACE1 activity restores the gain of spine density upon EE in deltaE9 mice, but not the remodeling of neural networks. On the other hand, anti-inflammatory treatment with pioglitazone or interleukin 1 receptor antagonist in deltaE9 mice successfully rescues the impairments in increasing spine density and remodeling of neural networks during EE. Our data suggest that neuroinflammation disrupts experience-dependent structural plasticity of dendritic spines in preclinical stages of AD.
Keywords:
APPswe/PS1deltaE9 mice; Dendritic spines; Neuroinflammation; Preclinical AD; Structural plasticity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / drug therapy
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Alzheimer Disease / immunology*
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Alzheimer Disease / pathology
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism
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Animals
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Anti-Inflammatory Agents / pharmacology
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Aspartic Acid Endopeptidases / genetics
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Aspartic Acid Endopeptidases / metabolism
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Dendritic Spines / drug effects
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Dendritic Spines / immunology*
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Dendritic Spines / pathology
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Disease Models, Animal
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Female
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Mice, Inbred C57BL
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Mice, Transgenic
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Neuroimmunomodulation / drug effects
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Neuroimmunomodulation / immunology*
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Neuronal Plasticity / drug effects
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Neuronal Plasticity / immunology*
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Pioglitazone
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Pyramidal Cells / drug effects
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Pyramidal Cells / immunology
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Pyramidal Cells / pathology
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Receptors, Interleukin-1 Type I / antagonists & inhibitors
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Receptors, Interleukin-1 Type I / metabolism
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Somatosensory Cortex / drug effects
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Somatosensory Cortex / immunology
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Somatosensory Cortex / pathology
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Thiazolidinediones / pharmacology
Substances
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Anti-Inflammatory Agents
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Receptors, Interleukin-1 Type I
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Thiazolidinediones
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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Bace1 protein, mouse
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Pioglitazone