Co-occurrence of Alzheimer's disease β-amyloid and tau pathologies at synapses
Introduction
Alzheimer's disease (AD) neuropathology is traditionally characterized by the abnormal deposition of Aβ in extracellular plaques and tau in intracellular tangles. More recently, early intraneuronal accumulation of Aβ42, the most pathogenic Aβ species, has been described in AD (Alafuzoff et al., 2008, Cataldo et al., 2004, D’Andrea et al., 2001, Gouras et al., 2000, Ohyagi et al., 2005), Down syndrome (Busciglio et al., 2002, Cataldo et al., 2004, Gouras et al., 2000, Gyure et al., 2001, Mori et al., 2002), and transgenic AD mouse models (Lord et al., 2006, Oakley et al., 2006, Oddo et al., 2003, Sheng et al., 2003, Shie et al., 2003, Stokin et al., 2005, Takahashi et al., 2002, Van Broeck et al., 2008, Wirths et al., 2001, Zerbinatti et al., 2006). Further, transgenic AD mice develop physiological and behavioral abnormalities prior to plaques (Chapman et al., 1999, Holcomb et al., 1998, Moechars et al., 1999) but concomitant with intraneuronal Aβ peptide accumulation (Bayer and Wirths, 2008, Billings et al., 2005, Cruz et al., 2006, Echeverria et al., 2004, Knobloch et al., 2007, Lord et al., 2006, Oddo et al., 2003), supporting that intraneuronal Aβ peptides are involved in the initiation of AD pathogenesis (Gouras et al., 2005).
Evidence supports that Aβ accumulation precedes and promotes tau pathology. Crossbreeding of mutant amyloid precursor protein (APP) transgenic mice with (Lewis et al., 2001) or intracerebral injection of Aβ into tau mutant transgenic mice (Gotz et al., 2001) led to enhanced tau pathology. In human brains with early AD changes or Down syndrome, intraneuronal Aβ42 accumulation in CA1 pyramidal cell bodies preceded hyperphosphorylation of tau (Gouras et al., 2000, Gyure et al., 2001). In the 3xTg-AD mouse harboring mutations in APP, tau and presenilin, intraneuronal Aβ accumulation in cell bodies preceded tau hyperphosphorylation, and Aβ antibodies reduced both Aβ and tau pathologies (Oddo et al., 2003, Oddo et al., 2004). Recent evidence that behavioral deficits in transgenic mouse models of AD can be attenuated by reduction in tau (Roberson et al., 2007) further underscores the relevance in elucidating the biological mechanism(s) linking Aβ and tau. Here we analyze the relation between Aβ42 and phosphorylated tau in two well-established transgenic mouse models of AD and utilize the anatomy of the hippocampus to co-localize both early Aβ42 accumulation and tau phosphorylation to synapses.
Section snippets
Antibodies
Aβ42 antibody AB5078P (Chemicon, Temecula, CA) is a rabbit polyclonal antibody directed against the C-terminus of Aβ42 that was previously biochemically characterized (Kamal et al., 2001). The specificity of this Aβ42 antibody was additionally shown by absence of immunofluorescence in cultured neurons derived from well-established APP knockout mice (Zheng et al., 1995) compared to wild-type mice (Almeida et al., 2006). The well-established antibody AT8 (Endogen, Rockford, IL) detects tau
Results
Since Aβ42 accumulates with aging especially in distal neurites of AD transgenic mouse brains (Takahashi et al., 2002, Takahashi et al., 2004), and since hyperphosphorylated tau localizes to dystrophic neurites around plaques in human subjects, as well as APP mutant transgenic mice (using antibodies AT8, PHF1, R27, R32 and Alz50) (Moechars et al., 1999, Otth et al., 2002, Sturchler-Pierrat et al., 1997), we investigated whether there was a relation between Aβ42 accumulation and
Discussion
The relationship between Aβ and tau is a central question in AD research, and synaptic alterations are the best correlate of cognitive dysfunction in AD (Coleman and Yao, 2003). Although plaques and tangles are not obviously linked to synapses, our work shows that Aβ and tau pathologies co-occur at synapses. Taking advantage of the well-defined anatomy of the hippocampus, we found that Aβ42 accumulation and the mislocalization and hyperphosphorylation of tau in the CA1 region occurred early and
Disclosure statement
All authors disclose that there are no actual or potential conflicts of interest including any financial, personal or other relationship with other people or organizations.
Acknowledgements
This work is supported by an Alzheimer's Association Zenith award, National Institutes of Health grants NS045677, AG027140, AG028174 (GKG) and HL18974 (TAM), and Helen & Robert Appel. We thank Drs. Claudia Almeida, Jordi Magrane and Davide Tampellini for helpful discussions. We thank Drs. Frank LaFerla, University of California at Irvine, and Karen H. Ashe, University of Minnesota, for the 3xTg-AD and Tg2576 mice, respectively. We thank Dr. Peter Davies, Albert Einstein University School of
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