Cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative diseases, including the abnormal accumulation of amyloid-β, one of the pathological hallmarks of Alzheimer disease (AD). Acyl-CoA:cholesterol acyltransferases (ACAT1 and ACAT2) are two enzymes that convert free cholesterol to cholesteryl esters. ACAT inhibitors have recently emerged as promising drug candidates for AD therapy. However, how ACAT inhibitors act in the brain has so far remained unclear. Here we show that ACAT1 is the major functional isoenzyme in the mouse brain. ACAT1 gene ablation (A1−) in triple transgenic (i.e., 3XTg-AD) mice leads to more than 60% reduction in full-length human APPswe as well as its proteolytic fragments, and ameliorates cognitive deficits. At 4 months of age, A1− causes a 32% content increase in 24-hydroxycholesterol (24SOH), the major oxysterol in the brain. It also causes a 65% protein content decrease in HMG-CoA reductase (HMGR) and a 28% decrease in sterol synthesis rate in AD mouse brains. In hippocampal neurons, A1− causes an increase in the 24SOH synthesis rate; treating hippocampal neuronal cells with 24SOH causes rapid declines in hAPP and in HMGR protein levels. A model is provided to explain our findings: in neurons, A1− causes increases in cholesterol and 24SOH contents in the endoplasmic reticulum, which cause reductions in hAPP and HMGR protein contents and lead to amelioration of amyloid pathology. Our study supports the potential of ACAT1 as a therapeutic target for treating certain forms of AD.Alzheimer disease | cholesterol esterification | lipid metabolism | oxysterols

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43 (47%) patients were still alive. The median prior irradiation dose to the skull base region was 6360 cGy for those without TLN and 6760 cGy for those with TLN (PZ.055). Median re-irradiation proton dose was 60 CGE without TLN and 7 0CGE with TLN (PZ.419). Twelve patients (13%) were found to have temporal lobe necrosis with median time to development of 8 months. Of these patients, 6 patients had right-sided TLN, 5 had left-sided, and 1 patient had bilateral TLN. The median total mean dose to 2 cc to the right temporal lobe was 51.87 CGE for those without TLN and 75.10 CGE for those with TLN (PZ.057); median max pixel dose to the right was 68.80 CGE without TLN and 110.13 CGE with TLN (PZ.040). On the left side, median total mean dose to 2 cc was 32.29 CGE with no TLN and 59 CGE with TLN (PZ.211) and median max pixel dose was 55.19 CGE without TLN and 71.34 CGE with TLN (PZ.560). All patients were determined to have grade 1 TLN per CTCAE 4.0 with only radiographic evidence and were clinically asymptomatic except for one patient with grade 2 toxicity requiring medical management with steroids. Conclusion: Among patients treated in the re-irradiation setting with proton therapy, 13% of patients developed TLN that was only apparent radiographically except for one who was treated medically. Analysis of more detailed dosimetric data with longer follow-up data are underway to better ascertain the significance of these findings.

Lipomas are common benign mesenchymal neoplasms. Although 13% of lipomas are found in the head and neck, only 0.6% have been reported in the larynx. Of all lipomas, the spindle cell variant is the least common. In the present study, we report a case of supraglottic spindle cell lipoma and review the literature of laryngeal spindle cell lipoma. A 35-year-old male presented with dysphagia and dyspnea and was found to have bilateral supraglottic lesions causing airway obstruction. The masses were resected endoscopically. Final pathology demonstrated mature adipocytes and spindle cells, with immunohistochemical patterns supportive of spindle cell lipoma. Spindle cell lipomas have rarely been reported in the upper airway. To our knowledge, this is the youngest patient reported to date. These lipomas are uncommon benign neoplasms and should be distinguished from aggressive mesenchymal neoplasms such as liposarcoma variants to guide appropriate conservative but curative therapy.