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 β peptide (Aβ), 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 human-induced 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 18, 2021
- Source ID
- 10.1523/jneurosci.2553-20.2021
Entities
People
- Alex Groisman
- Alexandra M. Balcer
- Andrea M Dickey
- Andrew R. Holder
- Angels Almenar-Queralt
- Brian G. Bober
- Brian P. Head
- Edgar Gutiérrez-Franco
- Elizabeth A. Roberts
- Lawrence S.B. Goldstein
- My Tran
- Rodrigo S. Chaves
- Sameer B Shah
Organizations
- Congressionally Directed Medical Research Programs