| First Author | Nakanishi N | Year | 2013 |
| Journal | J Neurosci | Volume | 33 |
| Issue | 35 | Pages | 14170-83 |
| PubMed ID | 23986251 | Mgi Jnum | J:201575 |
| Mgi Id | MGI:5514426 | Doi | 10.1523/JNEUROSCI.4646-10.2013 |
| Citation | Nakanishi N, et al. (2013) Synaptic protein alpha1-takusan mitigates amyloid-beta-induced synaptic loss via interaction with tau and postsynaptic density-95 at postsynaptic sites. J Neurosci 33(35):14170-83 |
| abstractText | The synaptic toxicity of soluble amyloid-beta (Abeta) oligomers plays a critical role in the pathophysiology of Alzheimer's disease (AD). Here we report that overexpressed alpha1-takusan, which we previously identified as a protein that enhances synaptic activity via interaction with PSD-95, mitigates oligomeric Abeta-induced synaptic loss. In contrast, takusan knockdown results in enhanced synaptic damage. alpha1-Takusan interacts with tau either directly or indirectly, and prevents Abeta-induced tau hyperphosphorylation and mitochondrial fragmentation. Deletion analysis identified the second domain (D2) within the takusan protein that is required for PSD-95 clustering and synaptic protection from Abeta. A 51 aa sequence linking D2 to the PDZ-binding C terminus was found to be as effective as full-length takusan in protecting synapses from Abeta-induced damage. Moreover, a sequence containing the D2 from the human protein discs large homolog 5, when linked to a C-terminal PDZ-binding motif, can also increase the clustering of PSD-95 in cortical dendrites. In summary, alpha1-takusan protects synapses from Abeta-induced insult via interaction with PSD-95 and tau. Thus, takusan-based protein sequences from either mouse or human may be of potential therapeutic benefit in AD. |
