APOE4 is the greatest genetic risk factor for late-onset Alzheimer’s disease (AD), increasing the risk of developing the disease by 3-fold in the 14% of the population that are carriers. Despite 25 years of research, the exact mechanisms underlying how APOE4 contributes to AD pathogenesis remain incompletely defined. APOE in the brain is primarily expressed by astrocytes and microglia, cell types that are now widely appreciated to play key roles in the pathogenesis of AD; thus, a picture is emerging wherein APOE4 disrupts normal glial cell biology, intersecting with changes that occur during normal aging to ultimately cause neurodegeneration and cognitive dysfunction. This review article will summarize how APOE4 alters specific pathways in astrocytes and microglia in the context of AD and the aging brain. APOE itself, as a secreted lipoprotein without enzymatic activity, may prove challenging to directly target therapeutically in the classical sense. Therefore, a deeper understanding of the underlying pathways responsible for APOE4 toxicity is needed so that more tractable pathways and drug targets can be identified to reduce APOE4-mediated disease risk.
DLK is a master regulator of axonal retraction and regeneration following neuronal injury and contributes to neurodegeneration in numerous animal models of disease, but the mechanisms by which DLK's pro‐degenerative actions are constrained in healthy neurons are not known. Data to this point demonstrates that DLK is constitutively expressed in post‐mitotic neurons where it is maintained in an inactive state. Once injury occurs, DLK protein is stabilized, phosphorylated, and liberated from inhibitory factors, allowing it to engage the mitogen‐activated protein kinase kinase 4 (MKK4) to phospho‐c‐Jun N‐terminal Kinase (JNK) signaling cascade to regulate apoptosis via phospho‐c‐jun (p‐c‐jun) and the integrated stress response (ISR) pathway via protein kinase R (PKR)‐like endoplasmic reticulum kinase (PERK). Here we report that DLK also functions in healthy neurons as it is constitutively active in the adult mouse cerebellum in the absence of injury. Mouse cerebellar granule cells express full‐length DLK protein predominantly in the axon terminals and post‐synaptic densities along with abundant nuclear p‐c‐jun. Pharmacological inhibition of DLK rapidly eliminates nearly all phospho‐Mkk4 and nuclear p‐c‐Jun within 2 hours, demonstrating that c‐jun phosphorylation is DLK dependent. To understand how DLK pathway activation differs between homeostatic signaling and disease response, we used western blotting and immunofluorescence to compare the DLK pathway between cerebellum, cortex, and hippocampus in rTg4510 mice, which express human P301L mutant tau in the forebrain where it leads to profound DLK activation and neurodegeneration, with non‐transgenic controls. p‐c‐jun is significantly higher in cerebellum and in the transgenic forebrain areas than in the non‐transgenic control forebrain confirming that it is constitutively expressed in the cerebellum and induced from lower basal levels by pathological tau. We next examined the PERK pathway, including phospho‐PERK, phospho‐eIF2a, and the induction of GADD34, ATF4, and CHOP. Like p‐c‐jun, PERK signaling was induced in the rTg4510 forebrain, but was not activated to the same extent in the cerebellum, suggesting that DLK signaling during disease involves enhanced PERK signaling. DLK to JNK signaling is orchestrated by the JNK interacting protein (JIP) scaffolding molecules, of which there are 3 members. In contrast to the forebrain, the cerebellum expresses very little JIP3, whereas JIP1 and JIP2 appear similar across regions. Therefore we hypothesize that JIP3 is required for the injury‐ and disease‐induced DLK signaling pathway. Transcriptomics are currently being utilized to elucidate the physiological relevance of constitutive DLK signaling in the cerebellum.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.