Biology subjects

Figueroa, H. Y.

Publications and source records attributed to Figueroa, H. Y..

3 recordsLinked to original sources

bioRxiv2026

Immunoproteasome Deficiency Impairs Microglial Clearance and Worsens Tau and Amyloid Pathology

Immunoproteasome induction is prominent in Alzheimers disease (AD), but whether it protects proteostasis or amplifies neuroinflammation remains unresolved. Here, we generated immunoproteasome-deficient PS19 tauopathy and APP/human tau double-knock-in mice by crossing each disease model with L7M1 mice lacking two immunoproteasome catalytic subunits. Immunoproteasome deficiency increased phospho-tau burden, exacerbated amyloid-{beta} pathology and heightened microglial reactivity without suppressing constitutive 26S proteasome activity. In primary microglia and longitudinal two-photon imaging, immunoproteasome-deficient microglia engaged and engulfed tau aggregate-bearing material but failed to resolve internalized cargo, revealing a post-engulfment degradative checkpoint. Single-nucleus transcriptomics identified a remodeled P2ry12low/Trem2high microglial state with impaired phagolysosomal and mitochondrial programs. Reanalysis of human single-nucleus transcriptomic datasets showed that reduced microglial immunoproteasome expression was associated with cargo-processing gene-program changes similar to those observed in immunoproteasome-deficient mouse microglia. Together, these findings identify immunoproteasome biogenesis as a protective glial stress response that supports microglial aggregate clearance in AD.

neuroscience↗

bioRxiv2020

GPCR-mediated clearance of tau in post-synaptic compartments attenuates tau pathology in vivo

Accumulation of pathological tau in synapses has been identified as an early pathogenic event in Alzheimers disease (AD) and correlates strongly with cognitive decline in patients with AD. Tau is a cytosolic, axonal protein. However, in the disease condition, tau accumulates in post-synaptic compartments and pre-synaptic terminals, either due to missorting within neurons, trans-synaptic transfer between neurons or due to failure of clearance systems in synapses. Using a sub-cellular fractionation assay, we show that progressive deposition of seed competent tau occurs predominantly in post-synaptic compartments in a tau transgenic mouse and in AD patient brain, making these neuronal structures particularly vulnerable to tau toxicity. Tau-mediated post-synaptic toxicity could be further exacerbated by impaired proteasome activity which we detected by measuring the levels of polyubiquitin chains that target proteins to proteasomal degradation. To combat the accumulation of tau and proteasome impairment at the subcellular level, we devised a therapeutic strategy of proteasome-mediated clearance of tau restricted to the post-synaptic compartment. Utilizing the pharmacology of GPCRs, we show that in vivo stimulation of the PAC1R receptor by its ligand can propagate intracellular PKA signaling leading to enhanced synaptic proteasome activity and reduced tau in the post-synaptic compartment. Over time, clearance of post-synaptic tau led to reduced tauopathy and cognitive decline in rTg4510 mice. Together, these results highlight a novel therapeutic strategy of targeting GPCRs that propagate cAMP/PKA signaling as a tool to activate proteolysis restricted to synapses to prevent the accumulation of tau in the early stages of AD.

neuroscience↗

bioRxiv2018

APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice

The {varepsilon}4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimers disease (AD). However, the reason for the association between APOE4 and AD remains unclear. While much of the research has focused on the ability of the apoE4 protein to increase the aggregation and decrease the clearance of A{beta}, there is also an abundance of data showing that APOE4 negatively impacts many additional processes in the brain, including bioenergetics. In order to gain a more comprehensive understanding of the APOE4s role in AD pathogenesis, we performed a multi-omic analysis of APOE4 vs. APOE3 expression in the entorhinal cortex (EC) and primary visual cortex (PVC) of aged APOE mice. These studies revealed region-specific alterations in several bioenergetic pathways, including oxidative phosphorylation (OxPhos), the TCA-cycle and fatty acid metabolism. Follow-up analysis utilizing the Seahorse platform revealed decreased mitochondrial respiration in the hippocampus and cortex of aged APOE4 vs. APOE3 mice, but not in the EC of these mice. Additional studies, as well as the original multi-omic data suggest that bioernergetic pathways in the EC of aged APOE mice may be differentially regulated by APOE4 expression. Given the importance of the EC as one of the first regions to be affected by AD pathology in humans, this differential bionenergetic regulation observed in the EC vs. other brain regions of aged APOE4 mice may play an important role in the pathogenesis of AD, particularly among APOE4 carriers.

neuroscience↗