Elsevier

Neurobiology of Disease

Volume 33, Issue 2, February 2009, Pages 213-220
Neurobiology of Disease

Passive immunotherapy rapidly increases structural plasticity in a mouse model of Alzheimer disease

https://doi.org/10.1016/j.nbd.2008.10.011Get rights and content

Abstract

Senile plaque-associated changes in neuronal connectivity such as altered neurite trajectory, dystrophic swellings, and synapse and dendritic spine loss are thought to contribute to cognitive dysfunction in Alzheimer's disease and mouse models. Immunotherapy to remove amyloid beta is a promising therapy that causes recovery of neurite trajectory and dystrophic neurites over a period of days. The acute effects of immunotherapy on neurite morphology at a time point when soluble amyloid has been cleared but dense plaques are not yet affected are unknown. To examine whether removal of soluble amyloid β (Aβ) has a therapeutic effect on dendritic spines, we explored spine dynamics within 1 h of applying a neutralizing anti Aβ antibody. This acute treatment caused a small but significant increase in dendritic spine formation in PDAPP brain far from plaques, without affecting spine plasticity near plaques or average dendritic spine density. These data support the hypothesis that removing toxic soluble forms of amyloid-beta rapidly increases structural plasticity possibly allowing functional recovery of neural circuits.

Introduction

Compelling evidence from rare familial cases of Alzheimer disease (AD) caused by alterations in the amyloid precursor protein or presenilin 1, which affects its cleavage, support the theory that amyloid-β (Aβ) processing and aggregation are central to the pathogenesis of AD (Selkoe, 2000). Plaque deposition is an early event in the disease process, however plaque burden does not correlate well with cognitive decline unlike synapse loss and neurofibrillary tangle pathology (Ingelsson et al., 2004, Spires and Hyman, 2004). Thus there is a pressing search for the link between amyloid and cognitive decline. Recent data support the idea that synaptotoxicity is mediated by soluble, oligomeric forms of Aβ (Cleary et al., 2005, Hsieh et al., 2006, Snyder et al., 2005), which may provide such a link.

Work in several mouse models of plaque deposition has shown a decrease in dendritic spine density near plaques (Lanz et al., 2003, Moolman et al., 2004, Spires et al., 2005, Tsai et al., 2004). This decrease is greatest near plaques and spine density increases to approximately 75% of control levels at distances of greater than 50 μm from the plaque surface (Spires et al., 2005, Spires-Jones et al., 2007), likely reflecting the local concentrations of soluble, plaque-associated synaptotoxic molecules. We recently demonstrated that in the Tg2576 model, loss of spines is due to a decrease in stability of spines near plaques. Spine formation and elimination were observed over 1 h and more spines were eliminated near plaques in Tg2576 mice than in control cortex or young Tg2576 animals (Spires-Jones et al., 2007). Spine loss near plaques could potentially be associated with the presence of soluble forms of Aβ, or with other phenomena such as the presence of activated astrocytes and microglia. In organotypic culture, addition of oligomeric Aβ causes rapid spine loss involving activation of NMDA receptors, calcineurin, and cofilin (Shankar et al., 2007). Removal of both NMDA receptors and AMPA receptors has also been implicated in Aβ induced spine loss in culture (Hsieh et al., 2006, Snyder et al., 2005).

To examine whether soluble forms of Aβ contribute to plaque-associated spine loss in vivo, we observed spine dynamics acutely after application of a neutralizing antibody. It has been well established that anti Aβ antibodies can clear plaques (Bard et al., 2000, Lombardo et al., 2003), restore neuritic architecture (Brendza et al., 2005, Lombardo et al., 2003), and prevent behavioral changes in APP transgenic mice (Dodart et al., 2002), but these events occur over days to weeks. By contrast, our current data suggest an acute therapeutic effect of Aβ neutralizing antibodies, strongly implicating soluble Aβ species as toxic to dendritic spines in vivo.

Section snippets

Animals and surgery

PDAPP animals transgenic for human amyloid precursor protein with the familial Alzheimer disease associated V717F mutation (Games et al., 1995) and non-transgenic littermate controls were used for this study. Mice were 15–19 months of age and had substantial plaque pathology. For surgeries and imaging, mice were anesthetized with avertin (1.3% 2,2,2-tribromoethanol, 0.8% tert-pentylalcohol; 250 mg/kg). Green fluorescent dextrans (3000mw Alexa-488, 50 μg/μL in PBS — molecular probes) were

Plaque-associated dendritic pathology in PDAPP cortex

Dendritic spine density is reduced near plaques in several mouse models (Lanz et al., 2003, Moolman et al., 2004, Spires et al., 2005, Tsai et al., 2004). Here we measured linear spine density in layers II–III of primary somatosensory cortex (apical branches of layer 3 and 5 pyramidal neurons filled with fluorescent dextrans) in PDAPP and control animals. We found that at baseline (before antibody treatment) PDAPP mice have reduced spine density in cortex compared to control animals (n = 1201

Discussion

Structural plasticity of dendritic spines is implicated in learning and memory. In particular, spines have been reported to be formed or enlarged with long-term potentiation and to shrink or disappear with long term depression over a time course of minutes to hours (Matsuzaki et al., 2004, Nagerl et al., 2004, Okamoto et al., 2004, Zhou et al., 2004). Exposure to enriched environments, which enhances performance on behavioral tests even in the context of neurodegeneration, is also associated

Acknowledgments

This work was supported by NIH grants AG08487, AG00277, a John D French Foundation Fellowship, and Alzheimer's Association Pioneer Award and grant EB00768.

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