Biology subjects

Amontree, M.

Publications and source records attributed to Amontree, M..

6 recordsLinked to original sources

bioRxiv2026

4-methylumbelliferone attenuates amyloid pathology and learning deficits in the APP/PS1 mouse model

4-Methylumbelliferone (4-MU) inhibits hyaluronic acid (HA) synthesis and is currently approved in Europe for biliary spasm. 4-MU administration reduces perineuronal nets (PNNs), and enzymatic degradation of PNNs in mouse models of Alzheimers disease (AD) attenuates memory impairment. Although 4-MU has therapeutic efficacy in rodent models of fibrosis and cancer, it has not been examined in an Alzheimers model. Here, we evaluated the impact of long-term 4-MU treatment in the APP/PS1 amyloid mouse model. From three months of age, mice were on either a vehicle or 4-MU-supplemented diet for 70 days or 52 weeks. Short and long-term 4-MU treatment decreased the soluble parenchymal A{beta}1-42/A{beta}1-40 ratio. Reductions in insoluble amyloid plaque were observed following 52 weeks of treatment. Extended 4-MU administration also reduced PNN intensity and ameliorated spatial memory deficits in APP/PS1 mice. These findings provide support for targeting brain extracellular matrix (ECM) as a therapeutic strategy for AD.

neuroscience↗

bioRxiv2025

Varied monoamine reuptake inhibitors reduce parvalbumin expression; implications for pyramidal cell disinhibition and enhanced neuroplasticity

First-line antidepressants are effective in a significant percent of individuals but a full understanding of how these therapeutics target specific endpoints is lacking. Prior work has shown that depression is associated with hippocampal atrophy and that antidepressants can increase neurotrophin levels to increase hippocampal neurogenesis as well as hippocampal pyramidal cell (PC) spine density and arbor. These effects likely contribute to amelioration of symptoms. A less well-explored possibility is that antidepressants concomitantly disinhibit hippocampal PC activity, which could also facilitate increased PC arbor, spinogenesis and/or activity. In accordance, previous studies have shown antidepressants can attenuate stress-induced upregulation of perineuronal nets (PNNs). PNNs are predominantly localized to parvalbumin (PV) expressing GABAergic interneurons and increase PV expression and neuronal activity. Though specific antidepressants have been explored for effects on regional PNN expression, the question of whether hippocampal PNN/ECM remodeling is a shared feature of varied antidepressant drugs and more importantly, of whether it is associated with significant hippocampal PV inhibition, has not been well-addressed. Herein we examine three monoamine reuptake inhibitors, fluoxetine, venlafaxine and viloxazine, in animal models for effects on PNN remodeling and PV expression, a proxy for PV activity. We observe shared effects of these therapeutics including the ability to increase PNN degrading effectors that can downregulate PV activity. Consistent with this, we observe shared effects of these drugs in terms of their ability to significantly reduce PV levels. These findings highlight the possibility that ECM remodeling and associated hippocampal PC disinhibition represent a shared feature of varied antidepressant medications.

neuroscience↗

bioRxiv2025

Increased levels of HAPLN2, which anchors dense extracellular matrix, in the hippocampus of APOE4 targeted replacement mice

Hyaluronan and proteoglycan link protein 2 (HAPLN2) / Brain link protein-1 (Bral1) is important for the binding of chondroitin sulfate proteoglycans (CSPGs) to hyaluronan and thus for the formation of specific types of brain extracellular matrix (ECM). It is also significantly increased with aging. Moreover, machine learning has identified it as a brain-derived protein most predictive of Alzheimers disease (AD). HAPLN2 binds to CSPGs that may sequester aggregation-prone proteins and also restrict neuronal plasticity. Because the apolipoprotein 4 (APOE4) allele increases AD risk, in the present study we have examined hippocampal lysates from APOE3 and APOE4 targeted replacement (TR) mice using unbiased proteomics, Western blot and hippocampal immunostaining. With proteomics, we observe that HAPLN2 is among the most significantly upregulated proteins in APOE4 mice. Prior work suggests HAPLN2 is particularly important to the assembly of perinodal matrix, and herein we show that it also co-localizes with Wisteria floribunda agglutinin (WFA) positive perineuronal nets (PNNs). PNNs represent a dense form of ECM that can increase GABAergic neurotransmission to alter overall excitatory/inhibitory (E/I) balance and neuronal oscillations important to mood and memory. Proteomics also detected elevated levels of high temperature requirement peptidase-1 (HTRA1), which accumulates in cerebral blood vessels harboring amyloid, in APOE4 mice. In Western blot studies, lysates from APOE4 mice also showed significantly reduced levels chondroitin-6 sulfated proteoglycans, which makes PNNs more susceptible to proteolysis and less inhibitory. In addition, immunostaining studies showed that levels of the PNN component aggrecan were increased in the hippocampus of APOE4 animals. Overall, these findings contribute to an emerging body of literature suggesting that brain extracellular matrix may be altered with aging and other risk factors for AD, and suggest that future studies should assess PNNs, peri-nodal structure and axonal conduction in the background of APOE4.

neuroscience↗

bioRxiv2025

CCL5/CCR5 signaling modulates depression-relevant behavior, neuronal oscillations, and long-term depression of synaptic activity.

Major depressive disorder (MDD) is a debilitating disorder, often associated with perseverative thinking and anxiety. Localized reductions in pyramidal cell activity may contribute to associated symptoms, and effective antidepressant treatments typically enhance overall neuronal excitation. CCL5 is a chemokine that has been shown to reduce excitatory-neuronal activity, and is also increased with MDD and conditions that increase MDD risk. Here, we investigate the CCL5/CCR5 axis for its ability to modulate depression-relevant endpoints that are diminished in MDD, including neuronal oscillations, as well as biochemical and behavioral correlates of the disorder. In comparison to wildtype mice, CCR5 knockouts had increased gamma and theta power, and stronger theta/high-gamma phase amplitude coupling during dark-cycle EEG recordings. Compared to strain-matched wildtype mice, CCR5 knockouts also demonstrated reduced anxiety, increased sucrose preference, and improved associative memory. Proteomic analysis of the hippocampus showed that CCR5 knockouts had reduced levels of the GABA receptor alpha-4 subunit, which mediates tonic inhibition and restricts pyramidal cell plasticity. In complementary primary neuronal culture studies, CCL5 diminished GSK-3{beta} activity and impaired NMDA-dependent long-term depression (LTD), a form of plasticity that promotes cognitive flexibility. In addition, CCL5 signaling increased parvalbumin expression in GABAergic neurons through a CCR5-dependent manner. In combination with the ability of CCR5 to restrain gamma oscillation power and LTD, our data raise the possibility that CCL5/CCR5 signaling inhibits neuronal excitation through increased PV+ interneuron activity. Moreover, data are consistent with the possibility that CCR5 antagonists might share the ability of established antidepressants to both increase PC excitation and reduce PC inhibition. Significance StatementMajor depressive disorder (MDD) is a global leading cause of disability, and is associated with increased chemokine activation and inflammation. In this study, we investigate how the CCR5/CCL5 chemokine axis regulates behavioral and cognitive endpoints associated with MDD. This study aims to provide insight to how chemokine signaling underlies mood and behavioral symptoms of neuropsychiatric disorders. We hope this research supports further investigation of CCR5 antagonists for MDD and related mood and anxiety disorders.

neuroscience↗

bioRxiv2025

MMP-2/9 inhibition modulates sharp wave abundance, inhibitory proteoglycan sulfation, and fear memory in juvenile zebrafish: relevance to affective disorders

Sharp wave ripple (SWR) events, present in diverse species, spontaneously occur in the hippocampus during quiescent restfulness and slow-wave sleep. SWRs comprise a negative deflection, the sharp wave (SW) event with an often-superimposed ripple (R) and are the neural correlates of memory consolidation and recall. The Anterodorsolateral lobe (ADL) (zebrafish hippocampal homologue) exhibits SW and SWR events, and since SWs initiate SWRs, their abundance typically shows the same directionality. In previous work, we observed matrix metalloproteinase-9 (MMP-9)-dependent effects on depression-relevant behaviors, perineuronal net (PNN) levels, and SWR abundance in the adult rodent hippocampus. Here, we investigate MMP-2/9-dependent effects on biochemical, behavioral, and neurophysiological endpoints in juvenile zebrafish and zebrafish at the transition from the late juvenile period to early adulthood. With MMP-2/9 inhibition, juvenile zebrafish showed reduced SW amplitude and abundance together with increased fear memory retention and reduced sociability. Juvenile zebrafish also showed an increased percentage of longer-duration SW events. Except for a reduction in SW amplitude, these changes were not observed at the transition from late juvenile to early adulthood. These changes were accompanied by increased levels of chondroitin sulfate (CS) proteoglycan 4-O-sulfation, which modulates PNNs and excitatory-to-inhibitory (E/I) balance. Discontinuation of MMP-2/9 inhibition in juvenile zebrafish normalized deficits in ADL SW abundance and sociability. Together, these findings show that MMP-2/9 significantly influences E/I balance and learning and memory during the highly plastic juvenile period in zebrafish. Findings also have relevance to an emerging appreciation of PNN changes that may contribute to altered neuronal oscillations and mood or cognition.

neuroscience↗

bioRxiv2022

CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice

The APOE4 allele increases the risk for Alzheimers disease (AD) in a dose-dependent manner and is also associated with cognitive decline in non-demented elderly controls. In mice with targeted gene replacement (TR) of murine APOE with human APOE3 or APOE4, the latter show reduced neuronal dendritic complexity and impaired learning. APOE4 TR mice also show reduced gamma oscillation power and sharp wave ripple (SWR) abundance, neuronal population activities important to learning and memory. Published work has shown that brain extracellular matrix (ECM) can reduce neuroplasticity as well as gamma power and SWR abundance, while attenuation of ECM can instead enhance these endpoints. In the present study we examine human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 individuals and brain lysates from APOE3 and APOE4 TR mice for levels of ECM effectors that can increase matrix deposition and restrict neuroplasticity. We find that CCL5, a molecule linked to ECM deposition in liver and kidney, is increased in CSF samples from APOE4 individuals. Levels of tissue inhibitor of metalloproteinases (TIMPs), which inhibit the activity of ECM-degrading enzymes, are also increased in APOE4 CSF as well as protein lysates from APOE4 TR mice. Importantly, as compared to wildtype/APOE4 heterozygotes, CCR5 knockout/APOE4 heterozygotes show reduced TIMP levels and enhanced EEG gamma power. The latter also show improved learning and memory, suggesting that the CCR5/CCL5 axis could represent a therapeutic target for APOE4 individuals.

neuroscience↗