Presynaptic accumulation of APP-CTFβ may contribute to synaptic dysfunction in Alzheimer’s disease
TL;DR
It is shown that endogenous APP and its proteolytic C-terminal fragments (APP-CTFs), the precursors of amyloid-β (Aβ), are enriched at excitatory synapses, and that APP processing generates functionally distinct intermediates at the synapse, i.e. presynaptic APP-CTFβ, which can accumulate in the active zone of excitatory synapses and promote neuronal network excitation/inhibition imbalance.
Abstract
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. Dysregulation of amyloid precursor protein (APP) proteolysis is involved in Alzheimer’s disease. This study shows that APP processing generates functionally distinct intermediates at the synapse, i.e. presynaptic APP-CTFβ, accumulation of which causes neuronal network hyperactivity, and extracellular amyloid-β (Aβ), which can counteract APP-CTFβ-induced network hyperactivity. Endogenous amyloidogenic processing of APP occurs at excitatory presynaptic active zones. Presynaptic APP-CTFβ accumulation promotes synaptic vesicle recruitment, neurotransmitter release, and neuronal network hyperactivity, independent of Aβ. Acute Aβ treatment attenuates APP-CTFβ-induced hyperactivity. APP-CTFβ oligomerization regulates PIP2 interactions and exposure of its C-terminal domain, providing a mechanism for enhanced vesicle recruitment. Alzheimer’s disease patient brains exhibit elevated synaptic APP-CTFβ and enlarged excitatory presynaptic boutons. Endogenous amyloidogenic processing of APP occurs at excitatory presynaptic active zones. Presynaptic APP-CTFβ accumulation promotes synaptic vesicle recruitment, neurotransmitter release, and neuronal network hyperactivity, independent of Aβ. Acute Aβ treatment attenuates APP-CTFβ-induced hyperactivity. APP-CTFβ oligomerization regulates PIP2 interactions and exposure of its C-terminal domain, providing a mechanism for enhanced vesicle recruitment. Alzheimer’s disease patient brains exhibit elevated synaptic APP-CTFβ and enlarged excitatory presynaptic boutons. APP-CTFβ, the precursor of amyloid-β, can accumulate in the active zone of excitatory synapses and promote neuronal network excitation/inhibition imbalance.