Gamma frequency entrainment attenuates amyloid load and modifies microglia

Changes in gamma oscillations (20-50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer's disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40 Hz), but not other frequencies, reduces levels of amyloid-β (Aβ)[subscript 1-40] and Aβ [subscript 1-42] isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with Aβ. Subsequently, we designed a non-invasive 40 Hz light-flickering regime that reduced Aβ[subscript 1-40] and Aβ[subscript 1-42] levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer's-disease-associated pathology.National Institutes of Health (U.S.) (Grant 1R01EY023173)National Institutes of Health (U.S.) (Grant 1DP1NS087724)National Institutes of Health (U.S.) (Grant RF1AG047661)National Institutes of Health (U.S.) (Grant ROIGM104948

2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), affect millions of people every year and so far, there are no therapeutic cures available. Even though animal and histological models have been of great aid in understanding disease mechanisms and identifying possible therapeutic strategies, in order to find disease-modifying solutions there is still a critical need for systems that can provide more predictive and physiologically relevant results. One possible avenue is the development of patient-derived models, e.g. by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), which can then be differentiated into any cell type for modelling. These systems contain key genetic information from the donors, and therefore have enormous potential as tools in the investigation of pathological mechanisms underlying disease phenotype, and progression, as well as in drug testing platforms. hiPSCs have been widely cultured in 2D systems, but in order to mimic human brain complexity, 3D models have been proposed as a more advanced alternative. This review will focus on the use of patient-derived hiPSCs to model AD, PD, HD and ALS. In brief, we will cover the available stem cells, types of 2D and 3D culture systems, existing models for neurodegenerative diseases, obstacles to model these diseases in vitro, and current perspectives in the field

Phase I Trial of Neoadjuvant Conformal Radiotherapy Plus Sorafenib for Patients with Locally Advanced Soft Tissue Sarcoma of the Extremity

INTRODUCTION: Despite effective local therapy with surgery and radiation (RT), approximately 50% of patients with high grade soft tissue sarcoma (STS) will relapse and die of disease. Since experimental data suggest a significant synergistic effect when anti-angiogenic targeted therapies, such as sorafenib, are combined with RT, we chose to evaluate preoperative combined modality sorafenib and conformal RT in a Phase I/II trial among patients with extremity STS amenable to treatment with curative intent. METHODS: For the Phase I trial, eight patients with intermediate or high grade STS > 5 cm in maximal dimension or low grade STS > 8 cm in maximal dimension received concomitant sorafenib (dose escalation cohort 1:200 bid, cohort 2:200/400 daily) and preoperative RT (50 Gy in 25 fractions). Sorafenib was continued during entire period of RT as tolerated. Surgical resection was completed four to six weeks following completion of neoadjuvant sorafenib/RT. Three sorafenib dose levels were planned. Primary endpoints of the Phase I trial were maximal tolerated dose and dose-limiting toxicity (DLT). RESULTS: Eight patients were enrolled in the Phase I (5 female, median age 44, 3 high grade pleomorphic, 2 myxoid/round cell liposarcoma, 3 other). Median tumor size was 16 cm (range 8–29), and all tumors were located in the lower extremity. Two of 5 patients treated at dose level 2 developed DLT consisting of grade 3 rash not tolerating drug reintroduction. Other grade 3 side effects included anemia, perirectal abscess, and SVT. Radiation toxicity (grade 1 or 2 dermatitis, N=8) and post-surgical complications (3 grade 3 wound complications) were comparable to historical controls and other series of preoperative RT monotherapy. Complete pathologic reponse (≥ 95% tumor necrosis) was observed in 3 patients (38%). CONCLUSION: Neoadjuvant sorafenib in combination with RT is tolerable and appears to demonstrate activity in locally advanced extremity STS. Further study to determine efficacy at dose level 1 is warranted. (NCT#00805727, ClinicalTrials.gov