RT Journal Article
SR Electronic
T1 Axonal Organelle Buildup from Loss of AP-4 Complex Function Causes Exacerbation of Amyloid Plaque Pathology and Gliosis in Alzheimer's Disease Mouse Model
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0445-24.2024
DO 10.1523/ENEURO.0445-24.2024
VO 11
IS 12
A1 Orlowski, Alex
A1 Karippaparambil, Joseph
A1 Paumier, Jean-Michel
A1 Ghanta, Shraddha
A1 Pallares, Eduardo
A1 Chandran, Rumamol
A1 Edmison, Daisy
A1 Tandukar, Jamuna
A1 Gao, Ruixuan
A1 Gowrishankar, Swetha
YR 2024
UL http://www.eneuro.org/content/11/12/ENEURO.0445-24.2024.abstract
AB Lysosomes and related precursor organelles robustly build up in swollen axons that surround amyloid plaques and disrupted axonal lysosome transport has been implicated in worsening Alzheimer's pathology. Our prior studies have revealed that loss of Adaptor protein-4 (AP-4) complex function, linked primarily to spastic paraplegia (HSP), leads to a similar build of lysosomes in structures we term “AP-4 dystrophies.” Surprisingly, these AP-4 dystrophies were also characterized by enrichment of components of APP processing machinery, β-site cleaving enzyme 1 (BACE1) and Presenilin 2. Our studies examining whether the abnormal axonal lysosome buildup resulting from AP-4 loss could lead to amyloidogenesis revealed that the loss of AP-4 complex function in an Alzheimer's disease model resulted in a strong increase in size and abundance of amyloid plaques in the hippocampus and corpus callosum as well as increased microglial association with the plaques. Interestingly, we found a further increase in enrichment of the secretase, BACE1, in the axonal swellings of the plaques of Alzheimer model mice lacking AP-4 complex compared with those having normal AP-4 complex function, suggestive of increased amyloidogenic processing under this condition. Additionally, the exacerbation of plaque pathology was region specific as it did not increase in the cortex. The burden of the AP-4 linked axonal dystrophies/AP-4 dystrophies was higher in the corpus callosum and hippocampus compared with the cortex, establishing the critical role of AP-4-dependent axonal lysosome transport and maturation in regulating amyloidogenic amyloid precursor protein processing.