Amyloid-beta, tau protein, and oxidative changes as a physiological compensatory mechanism to maintain CNS plasticity under Alzheimer's disease and other neurodegenerative conditions.

In this review, we propose that the neurodegenerative changes in the neurochemistry of amyloid-beta (Abeta) aggregation, tau phosphorylation, cytoskeleton rearrangement, oxidative stress, and lipid peroxidation in Alzheimer's disease (AD), and a number of other neurodegenerative diseases, are secondary pathological features. In fact, we believe that these phenomena represent natural compensatory mechanisms for impaired primary neurodegeneration, membrane dynamic deterioration, and/or associated failures of neurotransmission, synaptic function, and neuroplasticity. Physiologically, Abeta, lipid peroxidation, and tau protein may function to sense changes in activity-dependent membrane properties and therefore biochemically modulate membrane lipid homeostasis for more efficient synaptic action.

Vascular-targeted photodynamic therapy (VTP) of a canine-transmissible venereal tumour in a murine model with Pd-bacteriopheophorbide (WST09).

Abstract Treatment of canine-transmissible venereal tumour (CTVT) with local vascular-targeted photodynamic therapy (VTP) using Pd-bacteriopheophorbide (WST09) as a drug is suggested as an alternative to conventional chemotherapy. Male CD1 nude mice were subcutaneously grafted with the xenograft-transmissible canine venereal tumour (XTVT). The VTP protocol delivered once consisted of intravenous administration of WST09 (10 mg kg(-1)) followed by immediate local illumination with a diode laser (763 nm).

Noninvasive quantitative in vivo mapping and metabolism of boronophenylalanine (BPA) by nuclear magnetic resonance (NMR) spectroscopy and imaging.

10B-enriched L-p-boronophenylalanine (BPA) is one of the compounds used in boron neutron capture therapy (BNCT). In this study, several variations of nuclear magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) were applied to investigate the uptake, clearance and metabolism of the BPA-fructose complex (BPA-F) in normal mouse kidneys, rat oligodendroglioma xenografts, and rat blood. Localized 1H MRS was capable of following the uptake and clearance of BPA-F in mouse kidneys with temporal resolution of a few minutes, while 1H MRSI was used to image the BPA distribution in the kidney with a spatial resolution of 9 mm3.

Cholesterol homeostasis failure as a unifying cause of synaptic degeneration.

We previously showed that fine tuning of neural cholesterol dynamics is essential for basic synapse function, plasticity and behavior. Significant experimental evidence indicates that cholinergic function, ionotropic and metabotropic receptor machinery, excessive tau phosphorylation, the change of amyloid beta (Abeta or Abeta) biochemistry, neural oxidative stress reactions, and other features of neurodegeneration also depend on fine tuning of brain cholesterol homeostasis. This evidence suggest that (i) cholesterol homeostasis break is the unifying primary cause of sporadic and familial Alzheimer's disease (AD), neuromuscular diseases (particularly inclusion-body myositis), Niemann-Pick's type C disease and Down syndrome, and (ii) explains the overlap of neurodegenerative hallmarks across the spectrum of neurodegenerative diseases.

Photodynamic therapy of established prostatic adenocarcinoma with TOOKAD: a biphasic apparent diffusion coefficient change as potential early MRI response marker.

The goal of this study was to examine the use of diffusion-weighted magnetic resonance imaging (DW-MRI) for the assessment of early progression of photodamage induced by Pd-bacteriopheophorbide (TOOKAD)-based photodynamic therapy (PDT). TOOKAD is a novel second-generation photosensitizer for PDT of solid tumors developed in our laboratory and presently under clinical trials for prostate cancer (PC) therapy. Using the subcutaneous human prostate adenocarcinoma WISH-PC14 xenografts in nude mice as a model, a unique biphasic change in the apparent diffusion coefficient (ADC) was observed within the first 24 hours post-PDT, with initial decrease followed by an increase in ADC.

Bypass of tumor drug resistance by antivascular therapy.

Multidrug resistance (MDR) presents a major obstacle for the successful chemotherapy of cancer. Its emergence during chemotherapy is attributed to a selective process, which gives a growth advantage to MDR cells within the genetically unstable neoplastic cell population. The pleiotropic nature of clinical MDR poses a great difficulty for the development of treatment strategies that aim at blocking MDR at the tumor cell level.

Cholesterol, synaptic function and Alzheimer's disease.

We experimentally modeled neuronal cholesterol imbalance by creating an acute biochemical increase in cholesterol turnover in rat hippocampal slices. This kind of experimental set-up impairs the redistribution of cholesterol from one cell to another via lipoprotein transport. While increasing cholesterol removal or immediately afterwards, we evoked and recorded two brain waveforms, paired pulse facilitation (PPF) and long-term potentiation (LTP), which indicate neurotransmission and synaptic plasticity, respectively.

Photodynamic therapy with Pd-Bacteriopheophorbide (TOOKAD): successful in vivo treatment of human prostatic small cell carcinoma xenografts.

Small cell carcinoma of the prostate (SCCP), although relatively rare, is the most aggressive variant of prostate cancer, currently with no successful treatment. It was therefore tempting to evaluate the response of this violent malignancy and its bone lesions to Pd-Bacteriopheophorbide (TOOKAD)-based photodynamic therapy (PDT), already proven by us to efficiently eradicate other aggressive non-epithelial solid tumors. TOOKAD is a novel bacteriochlorophyll-derived, second-generation photosensitizer recently, developed by us for the treatment of bulky tumors.

The levels of soluble amyloid beta in different high density lipoprotein subfractions distinguish Alzheimer's and normal aging cerebrospinal fluid: implication for brain cholesterol pathology?

Several previous studies reported the association of the soluble form of amyloid beta (sA beta) protein, a major constituent of amyloid deposits in Alzheimer's disease (AD), with normal blood, cerebrospinal fluid (CSF) and central nervous system high density lipoproteins (HDLs). The present report aimed to elucidate the pattern of sA beta and apolipoprotein (apo) distribution in AD CSF-HDL subfractions. We studied AD CSF-HDL subfractions by SDS/PAGE and immunoblot analysis after CSF fractionation via density flotation ultracentrifugation.

In vivo imaging of the neutron capture therapy agent BSH in mice using (10)B MRI.

Boron neutron capture therapy (BNCT) is an experimental cancer treatment modality requiring the targeting of (10)B-enriched compounds to the tumor, which is then irradiated by low-energy neutrons. One of the boron-containing compounds used for this purpose is the mercaptoborane Na(2)B(12)H(11)SH (BSH). The first in vivo MR images of (10)B-enriched BSH are presented here.

Biphasic modulation of protein kinase C and enhanced cell toxicity by amyloid beta peptide and anoxia in neuronal cultures.

A major feature of Alzheimer's disease is the deposition of the amyloid beta peptide (Abeta) in the brain by mechanisms which remain unclear. One hypothesis suggests that oxidative stress and Abeta aggregation are interrelated processes. Protein kinase C, a major neuronal regulatory protein is activated after oxidative stress and is also altered in the Alzheimer's disease brain.

Alzheimer's Abeta1-40 peptide modulates lipid synthesis in neuronal cultures and intact rat fetal brain under normoxic and oxidative stress conditions.

The effect of amyloid beta (Abeta), the major constituent of the Alzheimer's (AD) brain on lipid metabolism was investigated in cultured nerve cells and in a fetal rat brain model. Differentiated (NGF) and undifferentiated PC12 cells or primary cerebral cell cultures were incubated with [14C]acetate in the absence or presence of Abeta1-40. Incorporation of label into lipid species was determined after lipid extraction and TLC separation.

Beta-amyloid: Alzheimer's disease and brain beta-amyloidoses.

This review considers some aspects of the biochemistry of beta-amyloid, a protein which produces insoluble deposits in the brain. These deposits are a specific morphological feature of Alzheimer's disease, Down's syndrome, and senile dementia. Our contribution to the concept of a soluble form of beta-amyloid as of a normal human protein is presented.

Alzheimer's amyloid beta interaction with normal human plasma high density lipoprotein: association with apolipoprotein and lipids.

We report studies of the interaction of Alzheimer's amyloid beta protein (A beta) with normal human plasma high density lipoprotein (HDL), aiming to clarify to which lipoprotein (LP) structural constituent (apolipoprotein or lipid) soluble A beta is primarily bound. Purified HDLs were incubated with biotinylated A beta 1-40 followed by LP repurification by size exclusion (SE) HPLC. SDS-PAGE, immunoblot and N-terminal sequence analysis of the biotin-A beta positive protein bands revealed that A beta is bound to many apolipoproteins of the HDL, mainly apoA-I, apoA-II, apoE and apoJ.

Alzheimer's soluble amyloid beta protein is secreted by HepG2 cells as an apolipoprotein.

Recently we reported that the soluble form of amyloid beta protein (sA beta) in normal human plasma and cerebrospinal fluid is associated with lipoprotein (LP) particles. In this paper we tested the sA beta secretion by cells in association with LP in the model of the human hepatoma HepG2 cell line. These cells secreted sA beta to the culture media and expressed intracellular sA beta immunoreactivity.

Multiple inhibitory effects of Alzheimer's peptide Abeta1-40 on lipid biosynthesis in cultured human HepG2 cells.

Herein we describe the inhibitory effect of the synthetic peptide Abeta1-40, homologous to the major high-density lipoprotein-associated species of Alzheimer's amyloid beta protein (Abeta), on lipid biosynthesis in human hepatic HepG2 cells. This culture synthesizes various lipids from [14C]acetate as a precursor. Treatment of cells with different concentrations of Abeta1-40 decreased the syntheses of various radiolabeled lipid species.

Biochemical characterization of Alzheimer's soluble amyloid beta protein in human cerebrospinal fluid: association with high density lipoproteins.

The soluble form of Alzheimer's amyloid beta protein (sA beta) is associated with high density lipoproteins (HDL) in normal human plasma (BBRC, 1994, 205, 1164-1171). Since sA beta is also present in cerebrospinal fluid (CSF) and the lipoprotein pattern of CSF is different from that of plasma, it was of interest to ascertain whether the interaction of sA beta with HDL also occurs in CSF. Normal human CSF lipoproteins were obtained by sequential flotation ultracentrifugation and analyzed for the presence of sA beta via immunoblot, size-exclusion chromatography, immunoelectron microscopy, N-terminal sequence and mass-spectrometry analyses.

Alzheimer's peptides A beta 1-40 and A beta 1-28 inhibit the plasma cholesterol esterification rate.

The amyloid fibrils of Alzheimer's disease and Down's syndrome amyloid deposits are composed mainly of aggregated amyloid beta protein (A beta) which also exists in a soluble form. It has been shown that both Alzheimer's disease and Down's syndrome share another common feature: the decrease in plasma cholesterol esterification in affected individuals. In the present work the effect of synthetic peptides A beta 1-40 and A beta 1-28 on normal human plasma cholesterol esterification rate was studied.

A 10-amino-acid sequence in the N-terminal A/B domain of thyroid hormone receptor alpha is essential for transcriptional activation and interaction with the general transcription factor TFIIB.

The effects of the thyroid hormone (3,5,3'-triiodo-L-thyronine [T3]) on gene transcription are mediated by nuclear T3 receptors (T3Rs). alpha- and beta-isoform T3Rs (T3R alpha and -beta) are expressed from different genes and are members of a superfamily of ligand-dependent transcription factors that also includes the receptors for steroid hormones, vitamin D, and retinoids. Although T3 activates transcription by mediating a conformational change in the C-terminal approximately 220-amino-acid ligand-binding domain (LBD), the fundamental mechanisms of T3R-mediated transcriptional activation remain to be determined.