Imagine you’re trying to build a sandcastle at the beach, but instead of having a strong foundation, the sand is slipping through your fingers. That’s how Alzheimer’s disease (AD) feels like for neurons in the brain. While we know that AD is associated with aging and characterized by the presence of amyloid plaques and neurofibrillary tangles, recent evidence points to problems in the connections between neurons, called synapses, as the true culprits behind the disease. In this study, scientists set out to investigate a protein called MET and its partner molecule called hepatocyte growth factor (HGF), which together play important roles in brain development and function. They found that in both mouse models of AD and in patients’ brains, levels of MET were reduced. By experimenting with brain slices and genetically modified mice, they discovered that decreased MET signaling leads to abnormalities in synaptic plasticity, a process that allows communication between neurons. These findings provide valuable insights into understanding the mechanisms of AD and offer potential targets for developing new therapies. To dive deeper into this fascinating research, check out the full article!

Alzheimer’s disease (AD) is a neurodegenerative disorder strongly associates with aging. While amyloid plagues and neurofibrillary tangles are pathological hallmarks of AD, recent evidence suggests synaptic dysfunction and physical loss may be the key mechanisms that determine the clinical syndrome and dementia onset. Currently, no effective therapy prevents neuropathological changes and cognitive decline. Neurotrophic factors and their receptors represent novel therapeutic targets to treat AD and dementia. Recent clinical literature revealed that MET receptor tyrosine kinase protein is reduced in AD patient’s brain. Activation of MET by its ligand hepatocyte growth factor (HGF) initiates pleiotropic signaling in the developing brain that promotes neurogenesis, survival, synaptogenesis, and plasticity. We hypothesize that if reduced MET signaling plays a role in AD pathogenesis, this might be reflected in the AD mouse models and as such provides opportunities for mechanistic studies on the role of HGF/MET in AD. Examining the 5XFAD mouse model revealed that MET protein exhibits age-dependent progressive reduction prior to overt neuronal pathology, which cannot be explained by indiscriminate loss of total synaptic proteins. In addition, genetic ablation of MET protein in cortical excitatory neurons exacerbates amyloid-related neuropathology in 5XFAD mice. We further found that HGF enhances prefrontal layer 5 neuron synaptic plasticity measured by long-term potentiation (LTP). However, the degree of LTP enhancement is significantly reduced in 5XFAD mice brain slices. Taken together, our study revealed that early reduction of HGF/MET signaling may contribute to the synaptic pathology observed in AD.

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