Although amyloid-beta peptide (Abeta) is the neurotoxic species implicated in the pathogenesis of Alzheimer's disease (AD), mechanisms through which intracellular Abeta impairs cellular properties, resulting in neuronal dysfunction, remain to be clarified. Here we demonstrate that intracellular Abeta is present in mitochondria from brains of transgenic mice with targeted neuronal overexpression of mutant human amyloid precursor protein and AD patients. Abeta progressively accumulates in mitochondria and is associated with diminished enzymatic activity of respiratory chain complexes (III and IV) and a reduction in the rate of oxygen consumption. Importantly, mitochondria-associated Abeta, principally Abeta42, was detected as early as 4 months, before extensive extracellular Abeta deposits. Our studies delineate a new means through which Abeta potentially impairs neuronal energetics, contributing to cellular dysfunction in AD.

Mitochondrial Aβ: a potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease

The role of 17 beta-hydroxysteroid dehydrogenases.

http://www.jbc.org/content/early/2003/12/12/jbc.M313308200.full.pdf

Human Cytosolic 3α-Hydroxysteroid Dehydrogenases of the Aldo-keto Reductase Superfamily Display Significant 3β-Hydroxysteroid Dehydrogenase Activity IMPLICATIONS FOR STEROID HORMONE METABOLISM AND ACTION

Integrated view on 17beta-hydroxysteroid dehydrogenases.

This review focuses on primary cultures of human prostatic epithelial cells and their applications as models of normal and malignant biological behavior. Current abilities to culture cells from normal tissues, from premalignant dysplastic lesions (prostatic intraepithelial neoplasia), from primary adenocarcinomas, and from metastases are described. Evidence for representation of the interrelated cells of the normal prostatic epithelium--stem cells, basal epithelial cells, secretory epithelial cells, transit amplifying cells and neuroendocrine cells--in primary cultures is presented. Comparisons between normal and cancer-derived primary cultures are made regarding biological activities relevant to carcinogenesis, such as proliferation, apoptosis, differentiation, senescence, adhesion, migration, invasion, steroid hormone metabolism, other metabolic pathways and angiogenesis. Analyses of tumor suppressor activity, differential gene expression and cytogenetics in primary cultures have revealed changes relevant to prostate cancer progression. Preclinical studies with primary cultures have provided information useful for designing new strategies for chemoprevention, chemotherapy, cytotoxin therapy, radiation therapy, gene therapy and imaging. While the behavior of normal primary cultures is often used as a basis for comparison with established, immortal prostate cancer cell lines, the most informative studies are performed with donor-matched pairs of normal and malignant primary cultures, grown under identical conditions. Challenges that remain to be addressed if the full potential of primary cultures as a model system is to be realized include isolation, culture and characterization of stem cells, improved methodology to induce or maintain a fully differentiated, androgen-responsive phenotype, and identification of cell surface antigens or other markers with which to purify pure populations of live cancer or premalignant cells apart from non-malignant epithelial cells prior to culture.

/pdf/primary-cell-cultures-as-models-of-prostate-cancer-12ll4tlect.pdf

Primary cell cultures as models of prostate cancer development.

Function of human brain short chain L-3-hydroxyacyl coenzyme A dehydrogenase in androgen metabolism.

The tissue distribution, subcellular localization, and metabolic functions of human 17β-hydroxysteroid dehydrogenase type 10/short chain l-3-hydroxyacyl-CoA dehydrogenase have been investigated. Human liver and gonads are abundant in this enzyme, but it is present in only negligible amounts in skeletal muscle. Its N-terminal sequence is a mitochondrial targeting sequence, but is not required for directing this protein to mitochondria.  Immunocytochemical studies demonstrate that this protein, which has been referred to as ER-associated amyloid β-binding protein (ERAB), is not detectable in the ER of normal tissues. We have established that protocols employed to investigate the subcellular distribution of ERAB yield ER fractions rich in mitochondria. Mitochondria-associated membrane fractions believed to be ER fractions were employed in ERAB/Aβ-binding alcohol dehydrogenase studies. The present studies establish that in normal tissues this protein is located in mitochondria. This feature distinguishes it from all known 17β-hydroxysteroid dehydrogenases, and endows mitochondria with the capability of modulating intracellular levels of the active forms of sex steroids.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1046/j.0014-2956.2001.02421.2421.x

Characterization and localization of human type10 17β-hydroxysteroid dehydrogenase

The alcohol dehydrogenase (ADH) activity of human shortchain l-3-hydroxyacyl-CoA dehydrogenase (SCHAD) has been characterized kinetically. The k cat of the purified enzyme was estimated to be 2.2 min’", with apparent K m values of 280 mM and 22lM for 2-propanol and NAD+, respectively. The k cat of the ADH activity was three orders of magnitude less than the l3-hydroxyacyl-CoA dehydrogenase activity but was comparable with that of the enzyme’s hydroxysteroid dehydrogenase (HSD) activity for oxidizing 17b-oestradiol [He, Merz, Mehta, Schulz and Yang (1999) J. Biol. Chem. 274, 15014‐15019]. However, the k cat values of intrinsic ADH and HSD activities of human SCHAD were found to be two orders of magnitude less than those reported for endoplasmic-reticulum-associated amyloid bpeptide-binding protein (ERAB) [Yan, Shi, Zhu, Fu, Zhu, Zhu, Gibson, Stern, Collison, Al-Mohanna et al. (1999) J. Biol. Chem. 274, 2145‐2156]. Since human SCHAD and ERAB apparently

/pdf/intrinsic-alcohol-dehydrogenase-and-hydroxysteroid-52irlobq6l.pdf

Ying-Zi Yang

Papers

Function of human brain short chain L-3-hydroxyacyl coenzyme A dehydrogenase in androgen metabolism.

Characterization and localization of human type10 17β-hydroxysteroid dehydrogenase

Intrinsic alcohol dehydrogenase and hydroxysteroid dehydrogenase activities of human mitochondrial short-chain L-3-hydroxyacyl-CoA dehydrogenase.

Type 10 17beta-hydroxysteroid dehydrogenase catalyzing the oxidation of steroid modulators of γ-aminobutyric acid type A receptors

Oxidative 3α-hydroxysteroid dehydrogenase activity of human type 10 17β-hydroxysteroid dehydrogenase