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Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models
A Y Hsia1, E Masliah, L McConlogue
1Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, CA 94143-0450, USA.
Abstract:
Autosomal dominant forms of familial Alzheimer's disease (FAD) are associated with increased production of the amyloid beta peptide, Abeta42, which is derived from the amyloid protein precursor (APP). In FAD, as well as in sporadic forms of the illness, Abeta peptides accumulate abnormally in the brain in the form of amyloid plaques. Here, we show that overexpression of FAD(717V-->F)-mutant human APP in neurons of transgenic mice decreases the density of presynaptic terminals and neurons well before these mice develop amyloid plaques. Electrophysiological recordings from the hippocampus revealed prominent deficits in synaptic transmission, which also preceded amyloid deposition by several months. Although in young mice, functional and structural neuronal deficits were of similar magnitude, functional deficits became predominant with advancing age. Increased Abeta production in the context of decreased overall APP expression, achieved by addition of the Swedish FAD mutation to the APP transgene in a second line of mice, further increased synaptic transmission deficits in young APP mice without plaques. These results suggest a neurotoxic effect of Abeta that is independent of plaque formation.
Insights
Familial Alzheimer's disease (FAD) involves amyloid beta peptide (Abeta) buildup. This study shows Abeta causes neuronal and synaptic deficits before amyloid plaques form, suggesting a plaque-independent neurotoxic effect.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Familial Alzheimer's disease (FAD) is linked to increased amyloid beta peptide (Abeta) production from the amyloid precursor protein (APP).
- Abeta peptides aggregate into amyloid plaques in both FAD and sporadic Alzheimer's disease (AD).
Purpose of the Study:
- To investigate the neurotoxic effects of amyloid precursor protein (APP) mutations associated with familial Alzheimer's disease (FAD).
- To determine if amyloid beta (Abeta) peptide exerts neurotoxic effects independent of amyloid plaque formation.
Main Methods:
- Overexpression of FAD(717V-->F)-mutant human APP in transgenic mouse neurons.
- Electrophysiological recordings in the hippocampus.
- Analysis of presynaptic terminal and neuronal density.
- Generation of a second mouse line with Swedish FAD mutation and reduced APP expression.
Main Results:
- Overexpression of mutant APP led to decreased presynaptic terminal and neuronal density before plaque formation.
- Synaptic transmission deficits were observed in the hippocampus preceding amyloid deposition.
- Functional deficits became more pronounced than structural deficits with age.
- Increased Abeta production exacerbated synaptic deficits in mice without plaques.
Conclusions:
- Amyloid beta (Abeta) peptides exhibit neurotoxicity independent of amyloid plaque formation.
- Early synaptic dysfunction precedes plaque pathology in familial Alzheimer's disease models.
- APP mutations contribute to neurodegeneration through Abeta-mediated mechanisms before gross plaque aggregation.