title: Synaptic protein α1-takusan mitigates amyloid-β-induced synaptic loss via interaction with tau and postsynaptic density-95 at postsynaptic sites.
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 overexpressed α1-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 prevents Aβ-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.
authors.affiliation: Del E. Web Center for Neuroscience, Aging, and Stem Cell Research, and Bioinformatics Shared Resource, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA. nnakanishi@sanfordburnham.org
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nakanishi
authors.forename: Scott D
authors.initials: SD
authors.lastname: Ryan
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhang
authors.forename: Adnan
authors.initials: A
authors.lastname: Khan
authors.forename: Timothy
authors.initials: T
authors.lastname: Holland
authors.forename: Eun-Gyung
authors.initials: EG
authors.lastname: Cho
authors.forename: Xiayu
authors.initials: X
authors.lastname: Huang
authors.forename: Francesca-Fang
authors.initials: FF
authors.lastname: Liao
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
authors.forename: Shichun
authors.initials: S
authors.lastname: Tu
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D000076122:Disks Large Homolog 4 Protein; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D054731:PDZ Domains; D051381:Rats; D013569:Synapses / Q000378:metabolism*; D055366:Synaptic Potentials; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; C114461:DLG5 protein, human; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; D016875:tau Proteins