Ilona Har-Paz, Elor Arieli, Anan Moran
Neurobiology of disease: April 28, 2021
Recent research has suggested that the E4 allele of apolipoprotein E (apoE4) contributes to neurological dysfunction before the clinical detection of late-onset Alzheimer’s disease (AD). Har-Paz and colleagues previously determined that apoE4 causes early structural deficits in cortical and subcortical regions using targeted replacement mouse models. In the current study, the authors sought to determine if these early structural deficits affect neuronal activity and learning. To address this, they recorded neuronal activity from 3-month-old humanized apoE4 (hApoE4) and wildtype rats before and after conditioned taste aversion (CTA) training. Consistent with previous results in mouse models, they found impaired learning in hApoE4 rats which correlated with attenuated neuronal activity. Thus, the article concludes that apoE4 may cause impaired neuronal plasticity early in life, which contributes to the onset of AD pathology later in life. Overall, the study offers a unique perspective on the impact of apoE4 in early neuronal activity and functional plasticity. While the mechanisms involved in apoE4-related structural plasticity remain elusive, these results highlight the importance of evaluating the impact of apoE4 on neuronal activity in young-adults. Understanding these mechanisms may identify potential targets for early interventions, as well as offer novel biomarkers for early clinical detection.
APOE genotype dependent molecular abnormalities in the cerebrovasculature of Alzheimer’s disease and age?matched non?demented brains
Joseph O. Ojo, Jon M. Reed, Gogce Crynen, Prashanthi Vallabhaneni, James Evans, Benjamin Shackleton, Maximillian Eisenbaum, Charis Ringland, Anastasia Edsell, Michael Mullan, Fiona Crawford, and Corbin Bachmeier
Molecular Brain: July 8, 2021
Previous reports suggest that the APOE4 genotype leads to impaired vascular amyloid clearance, however the influence of APOE isoforms on the molecular integrity of the cerebrovasculature remains largely unknown. Ojo and colleagues hypothesized that APOE-dependent abnormalities in protein expression in the cerebrovasculature could compromise their essential functions and increase their vulnerability to AD pathogenesis. To examine the influence of APOE on the molecular integrity of the cerebrovasculature, the authors used an unbiased approach with a proteomics platform to characterize biological changes in cerebrovessels of AD patients and healthy controls from different APOE genetic backgrounds. The most significant pathway changes observed occurred in EIF2 signaling, eIF4 regulation, 70S6K signaling, and mTOR signaling. In E3/E4 cases, cell-type specific analysis identified significant alterations in endothelial cells, astrocytes, and smooth muscle cells. Endothelial cells and astrocytes were also altered in E4/E4 cases. The authors suggest that these changes implicate a link between APOE4 and impaired autophagy, ER stress, and mitochondrial bioenergetics. Future studies will be necessary to distinguish whether these discovered molecular changes precede AD pathology, or if they are a direct consequence of amyloid or tau aggregation. Ojo and colleagues also note it will also be useful to incorporate phosphoproteomics analysis to further characterize these pathway changes in EIF2 and mTOR signaling. Overall, results of this study give novel information on genotype dependent proteomic changes on cerebrovascular dysfunction related to Alzheimer’s Disease which can be employed to generate new targets for drugs and therapies that protect the cerebrovasculature from AD pathogenesis.
Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms
Yang Shi, Prabhakar Sairam Andhey, Christina Ising, Kairuo Wang, Lisa L. Snipes, Kevin Boyer, Stephanie Lawson, Kaoru Yamada, Wei Qin, Melissa Manis, Javier Remolina Serrano, Bruno A. Benitez, Robert E. Schmidt, Maxim Artyomov, Jason D. Ulrich, David M. Holtzman
Neuron; August 4, 2021
https://doi.org/10.1016/j.neuron.2021.05.034ApoE plays a role in both tau pathogenesis and neurodegeneration by driving microglial activation, however, the exact mechanism of how apoE regulates microglia remains unclear. Shi and colleagues hypothesized that reducing extracellular apoE levels through the overexpression of low-density lipoprotein receptor (LDLR) could attenuate tau pathogenesis and microglial hyperactivation. The authors found that overexpression of LDLR in P301S mice reduced apoE and p-tau levels compared to P301S mice. Similarly, LDLR overexpression in microglia was able to downregulate ApoE expression and reduce microglial activation. Analysis of snRNAseq data revealed that overexpression of LRLR expands the pool of oligodendrocyte progenitor cells (OPCs), which may promote oligodendrocyte genesis and myelin integrity under neurodegenerative stress. Together these data suggest that microglial LDLR could be a novel target for manipulation of apoE levels and microglial function to reduce tau pathology. Contrary to these findings, a similar apoE metabolic receptor, LRP1, was previously shown to mediate tau uptake and significantly increase tau propagation. The authors mention that an exacerbation of early tau pathology was not observed in LDLR overexpressing mice prior to the activation of microglia, suggesting that LDLR may not directly affect tau propagation and the protective effects are due to regulation of microglia.