Biology subjects

Hark, T. J.

Publications and source records attributed to Hark, T. J..

3 recordsLinked to original sources

bioRxiv2024

Levetiracetam prevents Aβ42 production through SV2a-dependent modulation of App processing in Alzheimer's disease models

In Alzheimers disease (AD), amyloid-beta (A{beta}) peptides are produced by proteolytic cleavage of the amyloid precursor protein (APP), which can occur during synaptic vesicle (SV) cycling at presynapses. Precisely how amyloidogenic APP processing may impair presynaptic proteostasis and how to therapeutically target this process remains poorly understood. Using App knock-in mouse models of early A{beta} pathology, we found proteins with hampered degradation accumulate at presynaptic sites. At this mild pathological stage, amyloidogenic processing leads to accumulation of A{beta}42 inside SVs. To explore if targeting SVs modulates A{beta} accumulation, we investigated levetiracetam (Lev), a SV-binding small molecule drug that has shown promise in mitigating AD-related pathologies despite its mechanism of action being unclear. We discovered Lev reduces A{beta}42 levels by decreasing amyloidogenic processing of APP in a SV2a-dependent manner. Lev corrects SV protein levels and cycling, which results in increased surface localization of APP, where it favors processing via the non-amyloidogenic pathway. Using metabolic stable isotopes and mass spectrometry we confirmed that Lev prevents the production of A{beta}42 in vivo. In transgenic mice with aggressive pathology, electrophysiological and immunofluorescent microscopy analyses revealed that Lev treatment reduces SV cycling and minimizes synapse loss. Finally, we found that human Down syndrome brains with early A{beta} pathology, have elevated levels of presynaptic proteins, confirming a comparable presynaptic deficit in human brains. Taken together, we report a mechanism that highlights the therapeutic potential of Lev to modify the early stages of AD and represent a promising strategy to prevent A{beta}42 pathology before irreversible damage occurs. One Sentence SummaryWe discovered that the SV-binding drug levetiracetam prevents A{beta}42 production by modulating SV cycling which alters APP localization and thus proteolytic processing, highlighting its therapeutic potential for AD.

neuroscience↗

bioRxiv2021

Sex-Dependent Effects of Chronic Microdrive Implantation on Acquisition of Trace Eyeblink Conditioning

Neuroscience techniques, including in vivo recording, have allowed for a great expansion in knowledge; however, this technology may also affect the very phenomena researchers set out to investigate. Including both female and male mice in our associative learning experiments shed light on sex differences on the impact of chronic implantation of tetrodes on learning. While previous research showed intact female mice acquired trace eyeblink conditioning faster than male and ovariectomized females, implantation of chronic microdrive arrays showed sexually dimorphic effects on learning. Microdrive implanted male mice acquired the associative learning paradigm faster than both intact and ovariectomized females. These effects were not due to the weight of the drive alone, as there were no significant sex-differences in learning of animals that received "dummy drive" implants without tetrodes lowered into the brain. Tandem mass tag mass spectrometry and western blot analysis suggest that significant alterations in the MAPK pathway, acute inflammation, and brain derived neurotrophic factor may underlie these observed sex- and surgery-dependent effects on learning.

neuroscience↗

bioRxiv2017

Amyloid accumulation drives proteome-wide alterations in mouse models of Alzheimers disease like pathology

Amyloid beta (A{beta}) peptides impair multiple cellular pathways in the brain and play a causative role in Alzheimers disease (AD) pathology, but how the brain proteome is remodeled during this process is unknown. To identify new protein networks associated with AD-like pathology, we performed global quantitative proteomic analysis in three mouse models at pre- and post-symptomatic ages. Our analysis revealed a robust and consistent increase in Apolipoprotein E (ApoE) levels in nearly all transgenic brain regions with increased A{beta} levels. Taken together with prior findings on ApoE driving A{beta} accumulation, this analysis points to a pathological dysregulation of the ApoE-A{beta} axis. We also found dysregulation of protein networks involved in excitatory synaptic transmission consistent with AD pathophysiology. Targeted analysis of the AMPA receptor complex revealed a specific loss of TARP{gamma}-2, a key AMPA receptor trafficking protein. Expression of TARP{gamma}-2 in vivo in hAPP transgenic mice led to a restoration of AMPA currents. This database of proteome alterations represents a unique resource for the identification of protein alterations responsible for AD.\n\nHighlightsO_LIProteomic analysis of mouse brains with AD-like pathology reveals stark remodeling\nC_LIO_LIProteomic evidence points to a dysregulation of ApoE levels associated with A{beta} clearance rather than production\nC_LIO_LICo-expression analysis found distinctly impaired synapse and mitochondria modules\nC_LIO_LIIn-depth analyses of AMPAR complex points to loss of TARP{gamma}-2, which may compromise synapses in AD\nC_LI\n\neTOC BlurbProteome-wide profiling of brain tissue from three mouse models of AD-like pathology reveals A{beta}, brain region, and age dependent alterations of protein levels. This resource provides a new global protein expression atlas for the Alzheimers disease research community.

neuroscience↗