Synaptic Protein alpha 1-Takusan Mitigates Amyloid-beta-Induced Synaptic Loss via Interaction with Tau and Postsynaptic Density-95 at Postsynaptic Sites

The synaptic toxicity of soluble amyloid-beta (A beta) oligomers plays a critical role in the pathophysiology of Alzheimer's disease (AD). Here we report that overexpressed alpha 1-takusan, which we previously identified as a protein that enhances synaptic activity via interaction with PSD-95, mitigates oligomeric A beta-induced synaptic loss. In contrast, takusan knockdown results in enhanced synaptic damage. alpha 1-Takusan interacts with tau either directly or indirectly, and prevents A beta-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 A beta. 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 A beta-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, alpha 1-takusan protects synapses from A beta-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.