Alzheimer Disease: Lecanu L

Lecanu L, Papadopoulos V. · Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington DC, 20057, USA. · Recent Pat CNS Drug Discov. · Pubmed #18221222 No free full text.

Abstract: Neurodegenerative disease broadly includes many different diseases, such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's, dementias with Lewy bodies, post-traumatic brain injury, and stroke. Although few common physiopathological changes have been discovered among these conditions, the semiology (if known), the triggered molecular pathways that lead to the observed pathologies, and the symptomatology are essentially different. These differences entail that the treatments, both current and future, have disease-specific indications. This idea led us to believe than it would be quite impossible to comprehensively review the progress made in drug discovery for all the neurodegenerative diseases and, therefore, we focused our attention in this review on the cutting-edge patents that pertain to the treatment of Alzheimer's disease (AD). Basic science discoveries have identified new targets/leads that have led the scientific community to develop new research initiatives in order to develop novel therapeutics entities and approaches. The purpose of this review is to discuss, through cutting-edge patents, the emergence of potential future treatments of AD. We hope to provide the reader with a broader and better understanding of what could be new therapies for AD during the next decade.

Papadopoulos V, Lecanu L, Brown RC, Han Z, Yao ZX. · Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Northwest, Washington, DC 20057, USA. · Neuroscience. · Pubmed #16338086 No free full text.

Abstract: The peripheral-type benzodiazepine receptor is a mitochondrial protein expressed at high levels in steroid synthesizing tissues, including the glial cells of the brain. Peripheral-type benzodiazepine receptor binds cholesterol with high affinity and is a key element of the cholesterol mitochondrial import machinery responsible for supplying the substrate cholesterol to the first steroidogenic enzyme, thus initiating and maintaining neurosteroid biosynthesis. Neurosteroid formation and metabolism of steroid intermediates are critical components of normal brain function. Peripheral-type benzodiazepine receptor also binds with high affinity various classes of compounds. Upon ligand activation peripheral-type benzodiazepine receptor-dependent cholesterol transport into mitochondria is accelerated leading in increased formation of neuroactive steroids. These steroids, such as allopregnanolone, have been shown to be involved in various neurological disorders, such as anxiety and mood disorders. Thus, peripheral-type benzodiazepine receptor drug ligand-induced neuroactive steroid formation offers a means to regulate brain dysfunction. Peripheral-type benzodiazepine receptor basal expression is upregulated in a number of neuropathologies, including gliomas and neurodegenerative disorders, as well as in various forms of brain injury and inflammation. In Alzheimer's disease pathology neurosteroid biosynthesis is altered and a decrease in the intermediate 22R-hydroxycholesterol levels is observed. This steroid was found to exert neuroprotective properties against beta-amyloid neurotoxicity. Based on this observation, a stable spirostenol derivative showing to display neuroprotective properties was identified, suggesting that compounds developed based on critical intermediates of neurosteroid biosynthesis could offer novel means for neuroprotection. In conclusion, changes in peripheral-type benzodiazepine receptor and neurosteroid levels are part of the phenotype seen in neuropathology and neurological disorders and offer potential targets for new therapies.

Matsuoka Y, Jouroukhin Y, Gray AJ, Ma L, Hirata-Fukae C, Li HF, Feng L, Lecanu L, Walker BR, Planel E, Arancio O, Gozes I, Aisen PS. · Department of Neurology, Georgetown University Medical Center, 4000 Reservoir Road N.W., Washington, DC 20057, USA. · J Pharmacol Exp Ther. · Pubmed #18199809 links to  free full text

Abstract: Neurofibrillary tangles composed of aggregated, hyperphosphorylated tau in an abnormal conformation represent one of the major pathological hallmarks of Alzheimer's disease (AD) and other tauopathies. However, recent data suggest that the pathogenic processes leading to cognitive impairment occur before the formation of classic tangles. In the earliest stages of tauopathy, tau detaches from microtubules and accumulates in the cytosol of the somatodendritic compartment of cells. Either as a cause or an effect, tau becomes hyperphosphorylated and aggregates into paired helical filaments that comprise the tangles. To assess whether an agent that modulates microtubule function can inhibit the pathogenic process and prevent cognitive deficits in a transgenic mouse model with AD-relevant tau pathology, we administered the neuronal tubulin-preferring agent, NAPVSIPQ (NAP). Three months of treatment with NAP at an early-to-moderate stage of tauopathy reduced the levels of hyperphosphorylated soluble and insoluble tau. A 6-month course of treatment improved cognitive function. Although nonspecific tubulin-interacting agents commonly used for cancer therapy are associated with adverse effects due to their anti-mitotic activity, no adverse effects were found after 6 months of exposure to NAP. Our results suggest that neuronal microtubule interacting agents such as NAP may be useful therapeutic agents for the treatment or prevention of tauopathies.