Reduction of Soluble Aβ and Tau, but Not Soluble Aβ Alone, Ameliorates Cognitive Decline in Transgenic Mice with Plaques and Tangles

Salvatore Oddo,Vitaly Vasilevko,Antonella Caccamo,Masashi Kitazawa,David H Cribbs,Frank M Laferla

doi:10.1074/jbc.m608485200

Salvatore Oddo, Vitaly Vasilevko + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m608485200

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Abstract

Increasing evidence points to soluble assemblies of aggregating proteins as a major mediator of neuronal and synaptic dysfunction. In Alzheimer disease (AD), soluble amyloid-beta (Abeta) appears to be a key factor in inducing synaptic and cognitive abnormalities. Here we report the novel finding that soluble tau also plays a role in the cognitive decline in the presence of concomitant Abeta pathology. We describe improved cognitive function following a reduction in both soluble Abeta and tau levels after active or passive immunization in advanced aged 3xTg-AD mice that contain both amyloid plaques and neurofibrillary tangles (NFTs). Notably, reducing soluble Abeta alone did not improve the cognitive phenotype in mice with plaques and NFTs. Our results show that Abeta immunotherapy reduces soluble tau and ameliorates behavioral deficit in old transgenic mice.

Highlights

Ther exacerbates the cognitive decline in the presence of A␤ and other Alzheimer disease (AD)-related alterations
Increasing evidence suggests that soluble A␤ may be a key factor in inducing cognitive decline, to our knowledge, no firm experimental evidence has been presented to show a comparable role for soluble tau in an experimental mammalian system, in the presence of A␤ pathology
We have shown that the onset of cognitive deficits in the 3xTg-AD mice is caused by the buildup of non-fibrillar intraneuronal A␤, and its clearance via immunotherapy leads to cognitive improvement [6]

Summary

Introduction

Ther exacerbates the cognitive decline in the presence of A␤ and other AD-related alterations. Postmortem evaluation of AD brains has provided some correlational evidence linking these structures to the cognitive decline, with the general finding that tangles are a better correlate than plaques [7, 8] These types of studies have two inherent limitations. A critical issue that remains to be resolved is whether therapeutic interventions aimed at decreasing A␤ will suffice to improve cognition in the presence of established plaques and NFTs. Here we actively or passively immunized aged 3xTg-AD mice to determine whether it was possible to ameliorate their cognitive impairments in the presence of established plaques and NFTs. We report that reduction of both soluble A␤ and tau levels were required to rescue the cognitive impairments. These data suggest that soluble tau plays an important role in the cognitive impairments in aged 3xTg-AD mice and by extrapolation independent therapies aimed at further reducing its levels or restoring tau function may lead to even greater cognitive improvements in human patients

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