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P4–023: Regiospecific loss of essential lipids sphingosine 1‐phosphate and galactosylceramide early in Alzheimer's disease pathogenesis
Author(s) -
Don Anthony,
Kain Nupur,
Couttas Timothy,
Garner Brett
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.05.1411
Subject(s) - sphingolipid , pathogenesis , hippocampus , entorhinal cortex , alzheimer's disease , neurodegeneration , neurofibrillary tangle , biology , pathology , apolipoprotein e , medicine , endocrinology , neuroscience , disease , biochemistry , senile plaques
Pin1 alters the cis-trans isomerization of phosphorylated Ser/Thr-Pro motifs inamyloidprecursor protein (APP) and tau, facilitating the formation of plaques and tangles inAD.Conversely, restoration of Pin1 restores normal structure and function of tau, implicating the importance of Pin1 in neuronal protein regulation. Synaptic plasticity allows for an activatedNMDAreceptor to induce hundreds ofphosphorylatedSer/Thr-Pro motifs in several hundredPSDproteins. In this study, we observed Pin1 associations with synaptic proteins at dendritic rafts and the postsynaptic density (PSD), compared pathological changes of Pin1 in AD patients against controls, and demonstrated the effect of loss of Pin1 activity on synaptic proteins and structure. Methods: Human cortices from 12 AD patients and 10 age-matched controls were prepared using a tissue extraction protocol, followed by SDSPAGE, Western and Dot blot analyses. W e used Pin1 -/-, Pin1 shRNA or Pin1 inhibitor to alter theactivity ofPin1in cultured neurons. Immunocytochemistry and immunoblot were used to visualize and analyze Pin1-related changes in Shank proteins and dendritic spines.Results:We found that Pin1 protein, a common pathological cause linked to the products of misfolding proteins Ab and hyperphosphorylated tau, colocalizes with NMDA receptors and Shank3 proteins. Pin1 levels are pathologically altered at the synapse in AD patients, and loss of Pin1 activity may alter the function of glutamate receptors and the levels of Shank proteins and dendritic spines in AD brains. Interestingly, loss of Pin1 causes an increase in the neuronal toxicity of Ab oligomers and NMDA. Conclusions: This study indicates that loss of Pin1 activity may induce structural changes of dendritic spines and synaptic dysfunction in AD development. Pin1 may serve as a common therapeutic target in the treatment of synaptic dysfunction and proteinmisfoldingin preclinical AD. Pin1 may also play a common pathological role in the synapses of other neurodegenerative diseases.