The study of Alzheimer's disease (AD)-associated mutations has implicated dysregulation of amyloid precursor protein (APP) proteolysis in the disease. Brain recordings have revealed synaptic hyperexcitation during asymptomatic and early stages of AD, reverting to overinhibition as dementia progresses. Here, we show that endogenous APP and its proteolytic C-terminal fragments (APP-CTFs), the precursors of amyloid-β (Aβ), are enriched at excitatory synapses. Pharmacological modulation of endogenous APP metabolite levels suggests a role for APP-CTFs, in particular APP-CTFβ, in regulating glutamatergic synaptic transmission. Presynaptic accumulation of APP-CTFβ promotes its oligomerization, increases synaptic vesicle docking, and causes vesicle release defects, accompanied by enhanced neuronal network activity. Examination of post-mortem AD patient brains yields consistent results, namely, elevated APP-CTFβ levels at synaptic compartments and enlarged excitatory presynaptic boutons. Strikingly, acute application of Aβ preparations enriched in monomeric species counteracts APP-CTFβ-induced hyperexcitability. Our findings indicate a role for presynaptic APP-CTFβ in modulating excitatory synaptic function and network activity, suggesting that amyloidogenic APP processing intermediates may contribute to early synaptic alterations in Alzheimer's disease.
Physics-based models of biomolecular systems that explicitly represent biomolecular structure and mechanics, such as atomistic molecular dynamics simulations are well-established because experimental data has been available to iteratively improve and validate models. Now, simulations of the biological mesoscale are growing in importance because of the improvements in experimental tools to visualise this regime. This includes techniques such as cryo-electron microscopy and tomography, microscopies that follow individual proteins in their cellular contexts, in situ scattering to follow the dynamic evolution of biomolecular assembly, and -omics tools. Together, these approaches alone and in combination have revealed the importance of interactomes that bridge multiple scales. Here we describe the theoretical, computational and cultural challenges that need to be overcome to gain an understanding of the biological mesoscale and offer potential solutions. This commentary is the result of a joint CECAM/CCPBioSim discussion workshop on how the community should address the challenges of biomolecular simulations at the mesoscale held in Trento, Italy in the summer of 2024. The aim is to provide a broad overview of the tools and techniques relevant to the biological mesoscale, and to signpost the reader to more detailed discussions within the cited literature.
Sarah Harris, Gianluca Lattanzi, Angelo Rosa et al.· Biophysical Journal· 0 citations
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