Bexarotene normalizes chemotherapy-induced myelin decompaction and reverses cognitive and sensorimotor deficits in mice.

Frequently reported neurotoxic sequelae of cancer treatment include cognitive deficits and sensorimotor abnormalities that have long-lasting negative effects on the quality of life of an increasing number of cancer survivors. The underlying mechanisms are not fully understood and there is no effective treatment. We show here that cisplatin treatment of mice not only caused cognitive dysfunction but also impaired sensorimotor function. These functional deficits are associated with reduced myelin density and complexity in the cingulate and sensorimotor cortex. At the ultrastructural level, myelin abnormalities were characterized by decompaction. We used this model to examine the effect of bexarotene, an agonist of the RXR-family of nuclear receptors. Administration of only five daily doses of bexarotene after completion of cisplatin treatment was sufficient to normalize myelin density and fiber coherency and to restore myelin compaction in cingulate and sensorimotor cortex. Functionally, bexarotene normalized performance of cisplatin-treated mice in tests for cognitive and sensorimotor function. RNAseq analysis identified the TR/RXR pathway as one of the top canonical pathways activated by administration of bexarotene to cisplatin-treated mice. Bexarotene also activated neuregulin and netrin pathways that are implicated in myelin formation/maintenance, synaptic function and axonal guidance. In conclusion, short term treatment with bexarotene is sufficient to reverse the adverse effects of cisplatin on white matter structure, cognitive function, and sensorimotor performance. These encouraging findings warrant further studies into potential clinical translation and the underlying mechanisms of bexarotene for chemobrain.

Chemotherapy accelerates age-related development of tauopathy and results in loss of synaptic integrity and cognitive impairment.

Cancer and its treatment are associated with neurotoxic side effects, including cognitive dysfunction, altered functional connectivity in the brain and structural abnormalities in white matter. There is evidence that cancer and its treatment can accelerate aging. Tau is a microtubule associated protein that contributes to microtubule stability thereby playing a key role in neuronal function. Clustering of tau is commonly observed in the aged brain and is related to cognitive decline. We hypothesized that chemotherapy-induced cognitive impairment is associated with accelerated development of tau clustering in the brain as a sign of accelerated aging. We show for the first time that treatment of adult (7-8 month-old) male C57BL/6 mice with cisplatin results in reduced cognitive function and a marked increase in the number of large endogenous tau clusters in the hippocampus when assessed 4 months later. In contrast, we detected only few small tau clusters in the hippocampus of age-matched 11-12 month-old control mice. Astrocyte GFAP expression was increased in close vicinity to the tau clusters in cisplatin-treated mice. We did not detect changes in the microglial marker Iba-1 in the brain of mice treated with cisplatin. The accelerated formation of Tau-1 clusters in cisplatin-treated mice was associated with a decrease in the levels of the post-synaptic marker PSD95 and of the presynaptic marker synaptophysin in the hippocampus. We demonstrate here for the first time that chemotherapy markedly accelerates development of signs of tauopathy and loss of synaptic integrity in the hippocampus. These findings provide a mechanistic link between chemotherapy cognitive decline and accelerated aging in cancer survivors.

Nasal administration of mesenchymal stem cells restores cisplatin-induced cognitive impairment and brain damage in mice.

Cognitive impairments are a common side effect of chemotherapy that often persists long after treatment completion. There are no FDA-approved interventions to treat these cognitive deficits also called 'chemobrain'. We hypothesized that nasal administration of mesenchymal stem cells (MSC) reverses chemobrain. To test this hypothesis, we used a mouse model of cognitive deficits induced by cisplatin that we recently developed. Mice were treated with two cycles of cisplatin followed by nasal administration of MSC. Cisplatin treatment induced deficits in the puzzle box, novel object/place recognition and Y-maze tests, indicating cognitive impairment. Nasal MSC treatment fully reversed these cognitive deficits in males and females. MSC also reversed the cisplatin-induced damage to cortical myelin. Resting state functional MRI and connectome analysis revealed a decrease in characteristic path length after cisplatin, while MSC treatment increased path length in cisplatin-treated mice. MSCs enter the brain but did not survive longer than 12-72 hrs, indicating that they do not replace damaged tissue. RNA-sequencing analysis identified mitochondrial oxidative phosphorylation as a top pathway activated by MSC administration to cisplatin-treated mice. Consistently, MSC treatment restored the cisplatin-induced mitochondrial dysfunction and structural abnormalities in brain synaptosomes. Nasal administration of MSC did not interfere with the peripheral anti-tumor effect of cisplatin. In conclusion, nasal administration of MSC may represent a powerful, non-invasive, and safe regenerative treatment for resolution of chemobrain.

Discrete Pools of Oligomeric Amyloid-ß Track with Spatial Learning Deficits in a Mouse Model of Alzheimer Amyloidosis.

Despite increasing appreciation that oligomeric amyloid-ß (Aß) may contribute to cognitive decline of Alzheimer disease, defining the most critical forms has been thwarted by the changeable nature of these aggregates and the varying methods used for detection. Herein, using a broad approach, we quantified Aß oligomers during the evolution of cognitive deficits in an aggressive model of Aß amyloidosis. Amyloid precursor protein/tetracycline transactivator mice underwent behavioral testing at 3, 6, 9, and 12 months of age to evaluate spatial learning and memory, followed by histologic assessment of amyloid burden and biochemical characterization of oligomeric Aß species. Transgenic mice displayed progressive impairments in acquisition and immediate recall of the trained platform location. Biochemical analysis of cortical extracts from behaviorally tested mice revealed distinct age-dependent patterns of accumulation in multiple oligomeric species. Dot blot analysis demonstrated that nonfibrillar Aß oligomers were highly soluble and extracted into a fraction enriched for extracellular proteins, whereas prefibrillar species required high-detergent conditions to retrieve, consistent with membrane localization. Low-detergent extracts tested by 82E1 enzyme-linked immunosorbent assay confirmed the presence of bona fide Aß oligomers, whereas immunoprecipitation-Western blotting using high-detergent extracts revealed a variety of SDS-stable low-n species. These findings show that different Aß oligomers vary in solubility, consistent with distinct localization, and identify nonfibrillar Aß oligomer-positive aggregates as tracking most closely with cognitive decline in this model.

Impairments in experience-dependent scaling and stability of hippocampal place fields limit spatial learning in a mouse model of Alzheimer's disease.

Impaired spatial memory characterizes many mouse models for Alzheimer's disease, but we understand little about how this trait arises. Here, we use a transgenic model of amyloidosis to examine the relationship between behavioral performance in tests of spatial navigation and the function of hippocampal place cells. We find that amyloid precursor protein (APP) mice require considerably more training than controls to reach the same level of performance in a water maze task, and recall the trained location less well 24 h later. At a single cell level, place fields from control mice become more stable and spatially restricted with repeated exposure to a new environment, while those in APP mice improve less over time, ultimately producing a spatial code of lower resolution, accuracy, and reliability than controls. The limited refinement of place fields in APP mice likely contributes to their delayed water maze acquisition, and provides evidence for circuit dysfunction underlying cognitive impairment.