Richard Loeloff

Bio: Richard Loeloff is an academic researcher from Amgen. The author has contributed to research in topics: Bradykinin receptor & Receptor. The author has an hindex of 4, co-authored 4 publications receiving 4031 citations.

Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE.

Abstract: Cerebral deposition of amyloid beta peptide (Abeta) is an early and critical feature of Alzheimer's disease. Abeta generation depends on proteolytic cleavage of the amyloid precursor protein (APP) by two unknown proteases: beta-secretase and gamma-secretase. These proteases are prime therapeutic targets. A transmembrane aspartic protease with all the known characteristics of beta-secretase was cloned and characterized. Overexpression of this protease, termed BACE (for beta-site APP-cleaving enzyme) increased the amount of beta-secretase cleavage products, and these were cleaved exactly and only at known beta-secretase positions. Antisense inhibition of endogenous BACE messenger RNA decreased the amount of beta-secretase cleavage products, and purified BACE protein cleaved APP-derived substrates with the same sequence specificity as beta-secretase. Finally, the expression pattern and subcellular localization of BACE were consistent with that expected for beta-secretase. Future development of BACE inhibitors may prove beneficial for the treatment of Alzheimer's disease.

Potent nonpeptide antagonists of the bradykinin B1 receptor: structure-activity relationship studies with novel diaminochroman carboxamides.

Abstract: The bradykinin B1 receptor is induced following tissue injury and/or inflammation. Antagonists of this receptor have been studied as promising candidates for treatment of chronic pain. We have identified aryl sulfonamides containing a chiral chroman diamine moiety that are potent antagonists of the human B1 receptor. Our previously communicated lead, compound 2, served as a proof-of-concept molecule, but suffered from poor pharmacokinetic properties. With guidance from metabolic profiling, we performed structure-activity relationship studies and have identified potent analogs of 2. Variation of the sulfonamide moiety revealed a preference for 3- and 3,4-disubstituted aryl sulfonamides, while bulky secondary and tertiary amines were preferred at the benzylic amine position for potency at the B1 receptor. Modifying the beta-amino acid core of the molecule lead to the discovery of highly potent compounds with improved in vitro pharmacokinetic properties. The most potent analog at the human receptor, compound 38, was also active in a rabbit B1 receptor cellular assay. Furthermore, compound 38 displayed in vivo activity in two rabbit models, a pharmacodynamic model with a blood pressure readout and an efficacy model of inflammatory pain.

Alzheimer's Disease: Genes, Proteins, and Therapy

Abstract: Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...

Current concepts in mild cognitive impairment.

Abstract: The field of aging and dementia is focusing on the characterization of the earliest stages of cognitive impairment. Recent research has identified a transitional state between the cognitive changes of normal aging and Alzheimer's disease (AD), known as mild cognitive impairment (MCI). Mild cognitive impairment refers to the clinical condition between normal aging and AD in which persons experience memory loss to a greater extent than one would expect for age, yet they do not meet currently accepted criteria for clinically probable AD. When these persons are observed longitudinally, they progress to clinically probable AD at a considerably accelerated rate compared with healthy age-matched individuals. Consequently, this condition has been recognized as suitable for possible therapeutic intervention, and several multicenter international treatment trials are under way. Because this is a topic of intense interest, a group of experts on aging and MCI from around the world in the fields of neurology, psychiatry, geriatrics, neuropsychology, neuroimaging, neuropathology, clinical trials, and ethics was convened to summarize the current state of the field of MCI. Participants reviewed the world scientific literature on aging and MCI and summarized the various topics with respect to available evidence on MCI. Diagnostic criteria and clinical outcomes of these subjects are available in the literature. Mild cognitive impairment is believed to be a high-risk condition for the development of clinically probable AD. Heterogeneity in the use of the term was recognized, and subclassifications were suggested. While no treatments are recommended for MCI currently, clinical trials regarding potential therapies are under way. Recommendations concerning ethical issues in the diagnosis and the management of subjects with MCI were made.

A beta oligomers - a decade of discovery.

Abstract: Converging lines of evidence suggest that progressive accumulation of the amyloid beta-protein (A beta) plays a central role in the genesis of Alzheimer's disease, but it was long assumed that A beta had to be assembled into extracellular amyloid fibrils to exert its cytotoxic effects. Over the past decade, data have emerged from the use of synthetic A beta peptides, cell culture models, beta-amyloid precursor protein transgenic mice and human brain to suggest that pre-fibrillar, diffusible assemblies of A beta are also deleterious. Although the precise molecular identity of these soluble toxins remains unsettled, accumulating evidence suggests that soluble forms of A beta are indeed the proximate effectors of synapse loss and neuronal injury. Here we review recent progress in understanding the role of soluble oligomers in Alzheimer's disease.

The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics.

Abstract: The amyloid cascade hypothesis, which posits that the deposition of the amyloid-β peptide in the brain is a central event in Alzheimer's disease pathology, has dominated research for the past twenty years. Several therapeutics that were purported to reduce amyloid-β production or aggregation have failed in Phase III clinical testing, and many others are in various stages of development. Therefore, it is timely to review the science underpinning the amyloid cascade hypothesis, consider what type of clinical trials will constitute a valid test of this hypothesis and explore whether amyloid-β-directed therapeutics will provide the medicines that are urgently needed by society for treating this devastating disease.