Multiple Events Lead to Dendritic Spine Loss in Triple Transgenic Alzheimer's Disease Mice

Tobias Bittner,Gerda Mitteregger,Frank M Laferla,Hans Kretzschmar,Simon M Ochs,Nadine Hoffmann,Martin Fuhrmann,Steffen Burgold,Jochen Herms,Sven G Meuth

doi:10.1371/journal.pone.0015477

Tobias Bittner, Gerda Mitteregger + Show 8 more

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https://doi.org/10.1371/journal.pone.0015477

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Abstract

The pathology of Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptide, hyperphosphorylated tau protein, neuronal death, and synaptic loss. By means of long-term two-photon in vivo imaging and confocal imaging, we characterized the spatio-temporal pattern of dendritic spine loss for the first time in 3xTg-AD mice. These mice exhibit an early loss of layer III neurons at 4 months of age, at a time when only soluble Aβ is abundant. Later on, dendritic spines are lost around amyloid plaques once they appear at 13 months of age. At the same age, we observed spine loss also in areas apart from amyloid plaques. This plaque independent spine loss manifests exclusively at dystrophic dendrites that accumulate both soluble Aβ and hyperphosphorylated tau intracellularly. Collectively, our data shows that three spatio-temporally independent events contribute to a net loss of dendritic spines. These events coincided either with the occurrence of intracellular soluble or extracellular fibrillar Aβ alone, or the combination of intracellular soluble Aβ and hyperphosphorylated tau.

Highlights

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder
Soluble Ab can already be detected at 4 months of age in the hippocampus and cortex (Fig. S1A), but fibrillar amyloid plaques do not appear before 12 months of age (Fig. S1B)
Dendritic spine loss in the hippocampus Based on this spatio-temporal pattern of Ab and tau pathology, dendritic spine density was analyzed in the hippocampus and frontal cortex of 6, 10, 15, and 20 month old mice by confocal imaging in fixed slices (Fig. 1)

Summary

Introduction

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. Pathognomonic features include the accumulation of amyloid-b (Ab) peptide, hyperphosphorylated tau protein, neuronal death, and synaptic loss [1,2]. The abundance of soluble Ab levels in the cortex correlates positively with the first cognitive deficits and synaptic loss [12,13] long before fibrillar Ab plaques accumulate [1,14]. This has been modeled in AD transgenic mice that exhibit early synaptic loss and cognitive decline at a time, when only soluble Ab is present, but before amyloid plaques become abundant [15,16,17,18,19,20]. It is of great significance to understand how soluble Ab, insoluble amyloid plaques and hyperphosphorylated tau accumulation contribute to synaptic loss in AD

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