Amyloidogenic Processing of Amyloid Precursor Protein Drives Stretch-Induced Disruption of Axonal Transport in hiPSC-Derived Neurons

Abstract

Traumatic brain injury (TBI) results in disrupted brain function following impact from an external force and is a risk factor for sporadic Alzheimer's disease (AD). Although neurologic symptoms triggered by mild traumatic brain injuries (mTBI), the most common form of TBI, typically resolve rapidly, even an isolated mTBI event can increase the risk to develop AD. Aberrant accumulation of amyloid b peptide (Ab), a cleaved fragment of amyloid precursor protein (APP), is a key pathologic outcome designating the progression of AD following mTBI and has also been linked to impaired axonal transport. However, relationships among mTBI, amyloidogenesis, and axonal transport remain unclear, in part because of the dearth of human models to study the neuronal response following mTBI. Here, we implemented a custom-microfabricated device to deform neurons derived from humaninduced pluripotent stem cells, derived from a cognitively unimpaired male individual, to mimic the mild stretch experienced by neurons during mTBI. Although no cell lethality or cytoskeletal disruptions were observed, mild stretch was sufficient to stimulate rapid amyloidogenic processing of APP. This processing led to abrupt cessation of APP axonal transport and progressive formation of aberrant axonal accumulations that contained APP, its processing machinery, and amyloidogenic fragments. Consistent with this sequence of events, stretch-induced defects were abrogated by reducing amyloidogenesis either pharmacologically or genetically. In sum, we have uncovered a novel and manipulable stretch-induced amyloidogenic pathway directly responsible for APP axonal transport dysregulation. Our findings may help to understand and ultimately mitigate the risk of developing AD following mTBI.

Unraveling axonal mechanisms of traumatic brain injury

“…In case of extensive breakage and disintegration of microtubules, the axonal transport is expected to be completely interrupted. Live imaging recordings of the axonal transport immediately following injury in the present as well as in the previous studies, however, show only mildly impaired axonal transport [ 26 , 56 ]. Transport analyses of different cargos at later time points are needed to understand the long-term changes in transport and its relationship with AS.…”

“…For example, we didn’t observe APP accumulation during or immediately following injury, but we observed an increase in the intra-axonal Aβ42/Aβ40 ratio. Given the complex relationship between transport and APP processing, this could be the first step to aberrant Aβ accumulation as observed in a stretch in vitro model or in the post-mortem AS of individuals with TBI [ 56 , 61 ]. Also, immediately after injury, we observed phosphorylation changes in MAP1B (S1396 and S1400) and in NEFM (S837) in the axonal fraction.…”

Unraveling axonal mechanisms of traumatic brain injury

“…For example, we didn’t observe APP accumulation during or immediately following injury, but we observed an increase in the intra-axonal Aβ42/Aβ40 ratio. Given the complex relationship between transport and APP processing, this could be the first step to aberrant Aβ accumulation as observed in a stretch in vitro model or in the post-mortem AS of individuals with TBI (Chaves et al, 2021; Johnson et al, 2013). Also, immediately after injury, we observed phosphorylation changes in MAP1B (S1396 and S1400) and in NEFM (S837) in the axonal fraction.…”

The amyloid precursor protein regulates synaptic transmission at medial perforant path synapses

“…Presynaptic APP levels are regulated through anterograde axonal transport. Several studies have shown that anterograde axonal transport is affected early in neurodegenerative diseases which can promote amyloidogenesis (Bera et al, 2020; Chaves et al, 2021; Tang, 2009). Moreover, APP levels in the presynaptic compartment decrease upon disturbances in axonal transport during neurodegeneration (Morotz et al, 2019).…”