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 bioRxiv
FD Cold Spring Harbor Laboratory
SP 2024.03.31.587499
DO 10.1101/2024.03.31.587499
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://biorxiv.org/content/early/2024/11/11/2024.03.31.587499.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 build up 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 to 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 to the cortex, establishing the critical role of AP-4 -dependent axonal lysosome transport and maturation in regulating amyloidogenic amyloid precursor protein processing.Significance Statement A major pathological feature of Alzheimer’s disease is the accumulation of axonal lysosomes near sites of amyloid plaques. Lysosome accumulation is thought to contribute to amyloid production. In fact, a genetic perturbation that arrests lysosomes in axons exacerbates amyloid plaque pathology. The mechanisms that control axonal lysosome abundance as well the molecular composition of axonal endolysosomes that produce Abeta, however, are not fully understood. Axonal lysosome build-up is emerging as a common pathology in other neurodegenerative disorders such as Hereditary Spastic Paraplegia (HSP), but its relevance to amyloid production is unknown. We find that a model of HSP caused by loss of AP-4 adaptor complex lead to axonal lysosome buildup that differs in some of its content, but still contributes to amyloidogenesis. This demonstrates that different perturbations leading to changes in heterogeneous pool of axonal lysosomes can converge on a common pathology.Competing Interest StatementR.G. is a co-inventor of multiple patents related to expansion microscopy. The other authors declare that they have no competing financial interests.