Affiliations: [$] State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Cheng Du, China
| [a] Departments of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, USA
| [#] Nuclear Magnetic Resonance Laboratory, Molecular Structures group, School of Pharmacy, University of Kansas, Lawrence, KS, USA
Correspondence:
[*]
Correspondence to: Shi Fang Yan, MD, Higuchi Bioscience Center, University of Kansas, 2099 Constant Avenue, Lawrence, KS 66047, USA. Tel.: +1 785 864 1987; E-mail: sfangyan@ku.edu and Haiyang Yu, MD, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Cheng Du, 610041, China.
Note: [1] These authors contributed equally to this work.
Abstract: Loss of synapse and synaptic dysfunction contribute importantly to cognitive impairment in Alzheimer’s disease (AD). Mitochondrial dysfunction and oxidative stress are early pathological features in AD-affected brain. However, the effect of AD mitochondria on synaptogenesis remains to be determined. Using human trans-mitochondrial “cybrid” (cytoplasmic hybrid) neuronal cells whose mitochondria were transferred from platelets of patients with sporadic AD or age-matched non-AD subjects with relatively normal cognition, we provide the first evidence of mitochondrial dysfunction compromises synaptic development and formation of synapse in AD cybrid cells in response to chemical-induced neuronal differentiation. Compared to non-AD control cybrids, AD cybrid cells showed synaptic loss which was evidenced by a significant reduction in expression of two synaptic marker proteins: synaptophysin (presynaptic marker) and postsynaptic density protein-95, and neuronal proteins (MAP-2 and NeuN) upon neuronal differentiation. In parallel, AD-mediated synaptic deficits correlate to mitochondrial dysfunction and oxidative stress as well as activation of p38 MAP kinase. Notably, inhibition of p38 MAP kinase by pharmacological specific p38 inhibitor significantly increased synaptic density, improved mitochondrial function, and reduced oxidative stress. These results suggest that activation of p38 MAP kinase signaling pathway contributes to AD-mediated impairment in neurogenesis, possibly by inhibiting the neuronal differentiation. Our results provide new insight into the crosstalk of dysfunctional AD mitochondria to synaptic formation and maturation via activation of p38 MAP kinase. Therefore, blockade of p38 MAP kinase signal transduction could be a potential therapeutic strategy for AD by alleviating loss of synapses.
