Other
13 Authors
- Halabisky B,
- Palop JJ,
- Mucke L,
- Hamto P,
- Noebels JL,
- Yao J,
- Yu GQ,
- Devidze N,
- Roberson ED,
- Chin J,
- Yan F,
- Wu T,
- Yoo JW
| First Author | Roberson ED | Year | 2011 |
| Journal | J Neurosci | Volume | 31 |
| Issue | 2 | Pages | 700-11 |
| PubMed ID | 21228179 | Mgi Jnum | J:168226 |
| Mgi Id | MGI:4887484 | Doi | 10.1523/JNEUROSCI.4152-10.2011 |
| Citation | Roberson ED, et al. (2011) Amyloid-beta/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J Neurosci 31(2):700-11 |
| abstractText | Alzheimer's disease (AD), the most common neurodegenerative disorder, is a growing public health problem and still lacks effective treatments. Recent evidence suggests that microtubule-associated protein tau may mediate amyloid-beta peptide (Abeta) toxicity by modulating the tyrosine kinase Fyn. We showed previously that tau reduction prevents, and Fyn overexpression exacerbates, cognitive deficits in human amyloid precursor protein (hAPP) transgenic mice overexpressing Abeta. However, the mechanisms by which Abeta, tau, and Fyn cooperate in AD-related pathogenesis remain to be fully elucidated. Here we examined the synaptic and network effects of this pathogenic triad. Tau reduction prevented cognitive decline induced by synergistic effects of Abeta and Fyn. Tau reduction also prevented synaptic transmission and plasticity deficits in hAPP mice. Using electroencephalography to examine network effects, we found that tau reduction prevented spontaneous epileptiform activity in multiple lines of hAPP mice. Tau reduction also reduced the severity of spontaneous and chemically induced seizures in mice overexpressing both Abeta and Fyn. To better understand these protective effects, we recorded whole-cell currents in acute hippocampal slices from hAPP mice with and without tau. hAPP mice with tau had increased spontaneous and evoked excitatory currents, reduced inhibitory currents, and NMDA receptor dysfunction. Tau reduction increased inhibitory currents and normalized excitation/inhibition balance and NMDA receptor-mediated currents in hAPP mice. Our results indicate that Abeta, tau, and Fyn jointly impair synaptic and network function and suggest that disrupting the copathogenic relationship between these factors could be of therapeutic benefit. |
