Increased MANF expression contributes to synaptic dysfunctions in Alzheimer disease

The activation of endoplasmic reticulum (ER) stress is an early pathological hallmark of Alzheimer disease (AD) brain, but how ER stress contributes to the onset and development of AD remains poorly characterized. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a non-canonical neurotrophic factor and an ER stress inducible protein. In this study, we found that increased expression of MANF correlates with synapse loss in the hippocampus of AD mice. The ectopic expression of MANF in mice via transgenic or viral approaches causes synapse loss and defects in learning and memory. We also identified that MANF interacts with ELAV like RNA binding protein 2 (ELAVL2), and affects its binding to RNA transcripts that are involved in synaptic functions. Reducing MANF expression ameliorates the synaptic pathology in the hippocampus of AD mice. Together, our study established MANF as a mechanistic link between ER stress and synaptic dysfunctions in AD and hinted at MANF as a therapeutic target in AD treatment.