Biology subjects

Jakowec, M. W.

Publications and source records attributed to Jakowec, M. W..

6 recordsLinked to original sources

bioRxiv2026

Tau Disaggregation by a CNS-Permeable Small Molecule Reduces Fibril and Oligomer Burden and Preserves Proteostasis and Behavior

Pathological tau aggregates drive neuronal dysfunction in Alzheimer's disease (AD) and related tauopathies, yet no approved therapy eliminates existing tau neurofibrillary tangles. Here, we report the development of a coumarin-based small-molecule series that disaggregates tau fibrils and oligomers through a stacking-driven co-assembly mechanism. Structure-activity relationships identified PT-13 as a lead compound that inhibits tau seeding by AD brain-derived matter and reduces aggregate burden measured across both fibrillar and oligomeric tau species. Mechanistic studies demonstrate that disaggregation does not generate soluble oligomeric intermediates, addressing a central question in the field. PT-13 is brain-penetrant and well tolerated in vivo. In a tauopathy mouse model, PT-13 treatment reduces tau pathology while preserving behavioral function, proteasome capacity, and synaptic integrity. These findings establish small-molecule tau disaggregation as a viable therapeutic strategy and provide a molecular framework for the design of aggregate-directed therapeutics in neurodegeneration.

neuroscience↗

bioRxiv2023

Ivermectin increases striatal cholinergic activity to facilitate dopamine terminal function

Ivermectin (IVM) is a commonly prescribed antiparasitic treatment with pharmacological effects on invertebrate glutamate ion channels resulting in paralysis and death of invertebrates. However, it can also act as a modulator of some vertebrate ion channels and has shown promise in facilitating L-DOPA treatment in preclinical models of Parkinsons disease. The pharmacological effects of IVM on dopamine terminal function were tested, focusing on the role of two of IVMs potential targets: purinergic P2X4 and nicotinic acetylcholine receptors. Ivermectin enhanced electrochemical detection of dorsal striatum dopamine release. Although striatal P2X4 receptors were observed, IVM effects on dopamine release were not blocked by P2X4 receptor inactivation. In contrast, IVM attenuated nicotine effects on dopamine release, and antagonizing nicotinic receptors prevented IVM effects on dopamine release. IVM also enhanced striatal cholinergic interneuron firing. L-DOPA enhances dopamine release by increasing vesicular content. L-DOPA and IVM co-application further enhanced release but resulted in a reduction in the ratio between high and low frequency stimulations, suggesting that IVM is enhancing release largely through changes in terminal excitability and not vesicular content. Thus, IVM is increasing striatal dopamine release through enhanced cholinergic activity on dopamine terminals.

neuroscience↗

bioRxiv2023

Exercise alters cortico-basal ganglia network functional connectivity: A mesoscopic level analysis informed by anatomic parcellation defined in the mouse brain connectome

The basal ganglia are important modulators of the cognitive and motor benefits of exercise. However, the neural networks underlying these benefits remain poorly understood. Our study systematically analyzed exercise-associated changes in functional connectivity in the cortico-basal ganglia-thalamic network during the performance of a new motor task, with regions-of-interest defined based on mesoscopic domains recently defined in the mouse brain structural connectome. Mice were trained on a motorized treadmill for six weeks or remained sedentary (control), thereafter undergoing [14C]-2-deoxyglucose metabolic brain mapping during wheel walking. Regional cerebral glucose uptake (rCGU) was analyzed in 3-dimensional brains reconstructed from autoradiographic brain sections using statistical parametric mapping. Functional connectivity was assessed by inter-regional correlation of rCGU. Compared to controls, exercised animals showed broad decreases in rCGU in motor areas, but increases in limbic areas, as well as the visual and association cortices. In addition, exercised animals showed (i) increased positive connectivity within and between the motor cortex and caudoputamen (CP), (ii) newly emerged negative connectivity of the substantia nigra pars reticulata with the globus pallidus externus, and CP, and (iii) reduced functional connectivity of the prefrontal cortex (PFC). Increased functional connectivity in the motor circuit in the absence of increases in rCGU strongly suggests greater network efficiency, which is also supported by the reduced involvement of PFC-mediated cognitive control during the performance of a new motor task. Our study delineates exercise-associated changes in functional circuitry at the subregional level and provides a framework for understanding the effects of exercise on new motor learning.

neuroscience↗

bioRxiv2021

Knockdown of astrocytic monocarboxylate transporter 4 (MCT4) in the motor cortex leads to loss of dendritic spines and a deficit in motor learning

Monocarboxylate transporters (MCTs) shuttle molecules, including L-lactate, involved in metabolism and cell signaling of the central nervous system. Astrocyte-specific MCT4 is a key component of the astrocyte-neuron lactate shuttle (ANLS) and is important for neuroplasticity and learning of the hippocampus. However, the importance of astrocyte-specific MCT4 in neuroplasticity of the M1 primary motor cortex remains unknown. In this study, we investigated astrocyte-specific MCT4 in motor learning and neuroplasticity of the M1 primary motor cortex using a cell-type specific shRNA knockdown of MCT4. Knockdown of astrocyte-specific MCT4 resulted in impaired motor performance and learning on the accelerating rotarod. In addition, MCT4 knockdown was associated with a reduction of neuronal dendritic spine density and spine width and decreased protein expression of PSD95 and Arc. Using near-infrared-conjugated 2-deoxyglucose uptake as a surrogate marker for neuronal activity, MCT4 knockdown was also associated with decreased neuronal activity in the M1 primary motor cortex and associated motor regions including the dorsal striatum and ventral thalamus. Our study supports a potential role for astrocyte-specific MCT4 and the ANLS in the neuroplasticity of the M1 primary motor cortex. Targeting MCT4 may serve to enhance neuroplasticity and motor repair in several neurological disorders, including Parkinsons disease and stroke.

neuroscience↗

bioRxiv2020

Exogenous L-lactate promotes astrocyte plasticity but is not sufficient for enhancing striatal synaptogenesis or motor learning in mice

L-lactate is an energetic and signaling molecule that is key to the metabolic and neuroplastic connection between astrocytes and neurons and may be involved in exercise-induced neuroplasticity. This study sought to explore the role of L-lactate in astrocyte reactivity and neuroplasticity. Using in vitro cultures of primary astrocytes, we show L-lactate increased expression of plasticity-related genes, including neurotrophic factors, Bdnf, Gdnf, Cntf and the immediate early gene cFos. L-lactates promotion of neurotrophic factor expression may be mediated in part by the lactate receptor HCAR1 since application of the HCAR1 agonist 3,5-DHBA also increased expression of Bdnf in primary astrocytes. In vivo L-lactate administration to healthy mice caused a similar increase in the expression of plasticity-related genes as well as increased astrocyte morphological complexity in a region-specific manner, with increased astrocytic response found in the striatum but not the ectorhinal cortex, regions of the brain where increases in regional cerebral blood flow are increased or unaltered, respectively, with motor behavior. Additionally, L-lactate administration did not cause synaptogenesis or improve motor behavior based on the latency to fall on the accelerating rotarod, suggesting that L-lactate administration can initiate astrocyte-specific gene expression, but the activation of motor circuits is necessary to initiate striatal neuroplasticity. These results suggest that peripheral L-lactate is likely an important molecular component of exercise-induced neuroplasticity by acting in an astrocyte-specific manner to prime the brain for neuroplasticity.

neuroscience↗

bioRxiv2020

Cognitive Flexibility Deficits in Rats with Dorsomedial Striatal 6-OHDA Lesions Tested Using a 3-Choice Serial Reaction Time Task with Reversal Learning

Lesions of the dorsomedial striatum elicit deficits in cognitive flexibility that are an early feature of Parkinsons disease (PD), and presumably reflect alterations in frontostriatal processing. The current study aimed to examine deficits in cognitive flexibility in rats with bilateral 6-hydroxydopamine (6-OHDA) lesions in the dorsomedial striatum. While deficits in cognitive flexibility have previously been examined in rodent PD models using the cross-maze, T-maze, and a food-digging task, the current study is the first to examine such deficits using a 3-choice serial reaction time task (3-CSRT) with reversal learning (3-CSRT-R). Although the rate of acquisition in 3-CSRT was slower in lesioned compared to control rats, lesioned animals were able to acquire a level of accuracy comparable to that of control animals following 16 days of training. In contrast, substantial and persistent deficits were apparent during the reversal learning phase. Our results demonstrate that deficits in cognitive flexibility can be robustly unmasked by reversal learning in the 3-CSRT-R paradigm, which can be a useful test for evaluating effects of dorsomedial striatal deafferentation.

animal behavior and cognition↗