Synaptic protein α1-takusan mitigates amyloid-β-induced synaptic loss via interaction with tau and postsynaptic density-95 at postsynaptic sites

Nobuki Nakanishi, Scott D. Ryan, Xiaofei Zhang, Adnan Khan, Timothy Holland, Eun Gyung Cho, Xiayu Huang, Francesca-Fang Liao, Huaxi Xu, Stuart A. Lipton, Shichun Tu

Research output: Contribution to journalArticle

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Abstract

The synaptic toxicity of soluble amyloid-β (Aβ) oligomers plays a critical role in the pathophysiology of Alzheimer's disease (AD). Here we report that overexpressedα1-takusan, which we previously identified as a protein that enhances synaptic activity via interaction with PSD-95, mitigates oligomeric Aβ-induced synaptic loss. In contrast, takusan knockdown results in enhanced synaptic damage. α1- Takusan interacts with tau either directly or indirectly, and preventsAβ-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 Aβ. 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 Aβ-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,α1-takusan protects synapses from Aβ-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.

Original languageEnglish (US)
Pages (from-to)14170-14183
Number of pages14
JournalJournal of Neuroscience
Volume33
Issue number35
DOIs
StatePublished - Aug 30 2013

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Post-Synaptic Density
Amyloid
Synapses
Cluster Analysis
Alzheimer Disease
Proteins
Dendrites
Therapeutics

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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Synaptic protein α1-takusan mitigates amyloid-β-induced synaptic loss via interaction with tau and postsynaptic density-95 at postsynaptic sites. / Nakanishi, Nobuki; Ryan, Scott D.; Zhang, Xiaofei; Khan, Adnan; Holland, Timothy; Cho, Eun Gyung; Huang, Xiayu; Liao, Francesca-Fang; Xu, Huaxi; Lipton, Stuart A.; Tu, Shichun.

In: Journal of Neuroscience, Vol. 33, No. 35, 30.08.2013, p. 14170-14183.

Research output: Contribution to journalArticle

Nakanishi, Nobuki ; Ryan, Scott D. ; Zhang, Xiaofei ; Khan, Adnan ; Holland, Timothy ; Cho, Eun Gyung ; Huang, Xiayu ; Liao, Francesca-Fang ; Xu, Huaxi ; Lipton, Stuart A. ; Tu, Shichun. / Synaptic protein α1-takusan mitigates amyloid-β-induced synaptic loss via interaction with tau and postsynaptic density-95 at postsynaptic sites. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 35. pp. 14170-14183.
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