Amyloidogenic proteolysis of APP regulates glutamatergic presynaptic function
Akshay Kapadia, Postdoc at Hafner Lab - Molecular Dynamics of the Synapse, Donders Centre for Neuroscience, Radboud University, The Netherlands
Amyloid precursor protein (APP) is a 695-amino-acid transmembrane protein that undergoes sequential proteolysis within neurons to produce several biologically active fragments. The amyloidogenic pathway leads to the generation of APP-CTFβ, a membrane-bound C-terminal fragment, and eventually extracellular amyloid-β (Aβ) peptides.1 In Alzheimer’s disease (AD), this tightly regulated process becomes disrupted. AD is characterized by abnormal neural activity that shifts from excessive excitation in early stages to excessive inhibition as the disease progresses. These network imbalances have long been associated with the accumulation of Aβ, which is known for its neurotoxic properties. However, the role of intermediate processing fragments such as APP-CTFβ remains poorly understood.2
In this study, we show that APP-CTFβ preferentially accumulates at excitatory synapses—the primary sites of neuronal communication—and plays an important role in synaptic transmission. Using molecular and biochemical approaches to modulate APP processing, we demonstrate that accumulation of APP-CTFβ, and not APP or Aβ, triggers neuronal hyperactivity. We show that APP-CTFβ interacts with PI(4,5)P2 lipids and components of the vesicle release machinery. Notably, we find that Aβ can temporarily dampen this hyperactivity through an alternate mechanism.
These findings suggest a revised model of early AD pathophysiology in which APP-CTFβ, rather than Aβ, initiates network hyperactivity. Aβ may serve a compensatory role in dampening this overexcitation. Therapeutically, this implies that early clearance of Aβ could be detrimental by disrupting this compensatory feedback, highlighting the importance of timing in Aβ-targeting interventions.3
References:
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