RESUMEN
BACKGROUND: Alzheimer's disease (AD) features perturbed brain glucose utilization, which could contribute to brain bioenergetic failure. This led some to consider using ketone bodies to enhance AD brain bioenergetics and treat AD. OBJECTIVE: We evaluated the rate at which brain homogenates from persons with Alzheimer's disease (AD) metabolize D-ß-hydroxybutyrate (BHB). METHODS: We homogenized pieces of temporal cortex from frozen autopsy brains obtained from recently deceased AD subjects (nâ=â4), and age-matched subjects that did not have clinical AD (nâ=â3). Measuring the rate of CO2 production that followed the introduction of radiolabeled BHB to the homogenates yielded a BHB utilization rate. RESULTS: Compared to the control homogenates, the BHB-supported CO2 production rate was 66%lower in the AD homogenates (pâ<â0.05). CONCLUSIONS: AD brains can utilize BHB, albeit less robustly than control brains. In conjunction with a previous study that demonstrated reduced glucose utilization in AD brain homogenates, our BHB data provide further evidence of AD brain mitochondrial dysfunction or altered mitochondrial biology.
RESUMEN
Alzheimer's disease (AD) is the major cause of dementia, accounting for 50% to 70% of the late-onset patients, with 17 to 20 million affected. It is characterized by neurofibrillary tangles, neuronal loss, and amyloid plaques in tissues of the cortex, hippocampus, and amygdala. Apoptosis or programmed cell death appears in the progression of AD. In this study, we investigated the gene expression of 14 apoptotic genes (E2F1, p21/WAF, ICE-LAP3, Fas Antigen, CPP-32, GADD153, ICE-beta, c-Fos, c-Jun, Bax-alpha, Bcl-2, Bcl-(x)L, BAK, and p53) in 5 normal and 6 AD human hippocampal tissues, using reverse transcription-polymerase chain reaction. Our results show an upregulation of gene expression in AD patients for c-Fos and BAK. ICE-beta, c-Jun, Bax-alpha, Bcl-x(L), p53, and GADD153 were found to be upregulated in some AD samples but were not detected or downregulated in other AD or normal samples. No gene expression was found for E2F1 , p21/WAF, ICE-LAP3, Fas Antigen, CPP32, or Bcl-2. These results indicate significant increases in c-Fos , c-Jun, and Bak; therefore, we suggest that these genes may be critical in the apoptotic cascades of AD.
Asunto(s)
Enfermedad de Alzheimer/genética , Apoptosis/genética , Expresión Génica , Hipocampo/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Femenino , Genes fos , Genes jun , Hipocampo/patología , Humanos , Masculino , Persona de Mediana Edad , Transducción de Señal , Regulación hacia Arriba , Proteína Destructora del Antagonista Homólogo bcl-2/genética , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismoRESUMEN
BACKGROUND: Manganese-dependent superoxide dismutase (MnSOD) is a major defense mechanism against potential cellular damage by reactive oxygen species (ROS). We have reported increased lipid peroxidation and decreased Cu/Zn SOD enzymatic activity in the temporal cortex of Alzheimer's diseased (AD) brains. MATERIAL/METHODS: We now report the expression of MnSOD in the hippocampus of AD (n=8) and non-AD patients (n=7) via immunohistochemical methods, in both neuronal and non neuronal cells. We tested the hypothesis that there is differential expression of MnSOD in the CA1, CA2/3, and CA4 region of the hippocampus which may account for the neuronal loss seen in Alzheimer's disease. For neuronal cells, profile counts were made and expressed as positive neuronal profiles (MnSOD-IR) per mm(2) within hippocampal regions CA1, CA2/3, and CA4. RESULTS: The AD MnSOD-IR counts were over 9-fold higher in the CA2/3 region (p<0.001) and over 11-fold higher in the CA4 (p<0.001) region when compared to non-AD samples. The CA1 region in the AD samples showed the smallest increase (3-fold; p<0.05) when compared to non-AD patients. CONCLUSIONS: Since the CA1 region in AD is the most severely affected by the disease, our results suggest that normal compensatory mechanisms may be insufficient to protect this region from free radical oxidative damage.