NIH PubMed latest 20 review articles on Alzheimer's

Protease inhibitors: A panacea?

Haq SK, Rabbani G, Ahmad E, Atif SM, Khan RH

Protease inhibitors: A panacea?

J Biochem Mol Toxicol. 2010 Feb 4;

Authors: Haq SK, Rabbani G, Ahmad E, Atif SM, Khan RH

With the increasing evidence of protease involvement in several diseases, novel strategies for drug development involve the use of protease inhibitors (PIs). The local balance between protease inhibitors and proteases is an important determinant of the occurrence and progression of a particular disease. Hence, enzymes and their cognate inhibitors are finding their applications as diagnostic and prognostic markers. PIs are widely implicated for their use in host defense against infection, tissue repair and matrix production, blood coagulation, cancer, and they are, therefore, the current focus as therapeutic alternatives for major diseases such as AIDS and Alzheimer's diseases. This review is a brief summary of the varied role of protein protease inhibitors in controlling the activity of aberrant enzymes in several diseases afflicting mankind today. (c) 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 00:1-8, 2010; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20335.

PMID: 20135636 [PubMed - as supplied by publisher]

Vesicular monoamine transporters: Structure-function, pharmacology, and medicinal chemistry.

Wimalasena K

Vesicular monoamine transporters: Structure-function, pharmacology, and medicinal chemistry.

Med Res Rev. 2010 Feb 4;

Authors: Wimalasena K

Vesicular monoamine transporters (VMAT) are responsible for the uptake of cytosolic monoamines into synaptic vesicles in monoaminergic neurons. Two closely related VMATs with distinct pharmacological properties and tissue distributions have been characterized. VMAT1 is preferentially expressed in neuroendocrine cells and VMAT2 is primarily expressed in the CNS. The neurotoxicity and addictive properties of various psychostimulants have been attributed, at least partly, to their interference with VMAT2 functions. The quantitative assessment of the VMAT2 density by PET scanning has been clinically useful for early diagnosis and monitoring of the progression of Parkinson's and Alzheimer's diseases and drug addiction. The classical VMAT2 inhibitor, tetrabenazine, has long been used for the treatment of chorea associated with Huntington's disease in the United Kingdom, Canada, and Australia, and recently approved in the United States. The VMAT2 imaging may also be useful for exploiting the onset of diabetes mellitus, as VMAT2 is also expressed in the beta-cells of the pancreas. VMAT1 gene SLC18A1 is a locus with strong evidence of linkage with schizophrenia and, thus, the polymorphic forms of the VMAT1 gene may confer susceptibility to schizophrenia. This review summarizes the current understanding of the structure-function relationships of VMAT2, and the role of VMAT2 on addiction and psychostimulant-induced neurotoxicity, and the therapeutic and diagnostic applications of specific VMAT2 ligands. The evidence for the linkage of VMAT1 gene with schizophrenia and bipolar disorder I is also discussed. (c) 2010 Wiley Periodicals, Inc. Med Res Rev.

PMID: 20135628 [PubMed - as supplied by publisher]

Association of phosphatidylcholine and NSAIDs as a novel strategy to reduce gastrointestinal toxicity.

Lichtenberger LM, Barron M, Marathi U

Association of phosphatidylcholine and NSAIDs as a novel strategy to reduce gastrointestinal toxicity.

Drugs Today (Barc). 2009 Dec;45(12):877-90

Authors: Lichtenberger LM, Barron M, Marathi U

Nonsteroidal anti-inflammatory drugs (NSAIDs) are highly effective drugs that inhibit pain and inflammation, and perhaps due to the role of inflammation in the underlying etiology, NSAIDs have also demonstrated efficacy in reducing a patient's risk of developing a number of cancers and neurological diseases (e.g. Alzheimer's disease). The utility of these powerful drugs is limited due to their gastrointestinal (GI) side-effects, notably peptic ulceration and GI bleeding which is briefly reviewed here. We also describe the barrier property of the GI mucosa and how it is affected by NSAIDs, as it is our position that disruption of the surface barrier is an important component in the drugs' pathogenesis, in addition to selective inhibition of COX-2, which has proven to be problematic. We also discuss current alternative approaches being taken to mitigate the GI side-effects of NSAIDs, including developing combination drugs where NSAIDs are packaged with inhibitors of HCl secretion such as proton pump inhibitors or H2-receptor antagonists. We then present the rationale for the development of the PC associated NSAID technology which came out of our observation that the mammalian gastric mucosa has hydrophobic, nonwettable properties that provides a barrier to luminal acid, and the role of phospholipids and specifically phosphatidylcholine (PC) in this barrier property. In the last section we review the development of our current lipid-based PC-NSAID formulations and our encouraging preclinical and clinical observations validating their GI safety and therapeutic efficacy.

PMID: 20135022 [PubMed - in process]

Docosahexaenoic acid (DHA). Monograph.

Docosahexaenoic acid (DHA). Monograph.

Altern Med Rev. 2009 Dec;14(4):391-9

Authors:

PMID: 20030466 [PubMed - indexed for MEDLINE]

The relationship between Alzheimer's disease and diabetes: Type 3 diabetes?

Kroner Z

The relationship between Alzheimer's disease and diabetes: Type 3 diabetes?

Altern Med Rev. 2009 Dec;14(4):373-9

Authors: Kroner Z

In recent years, Alzheimer's disease (AD) has been considered to be, in part, a neuroendocrine disorder, even referred to by some as type 3 diabetes. Insulin functions by controlling neurotransmitter release processes at the synapses and activating signaling pathways associated with learning and long-term memory. Novel research demonstrates that impaired insulin signaling may be implicated in AD. Post-mortem brain studies show that insulin expression is inversely proportional to the Braak stage of AD progression. It was also demonstrated that neurotoxins, coined amyloid beta-derived diffusible ligands (ADDLs), disrupt signal transduction at synapses, making the cell insulin resistant. ADDLs reduce plasticity of the synapse, potentiate synapse loss, contribute to oxidative damage, and cause AD-type tau hyperphosphorylation. Diabetes and AD have signs of increased oxidative stress in common, including advanced glycation end products (AGEs), when compared to normal subjects. Diabetic patients appear to have an increased risk for AD because AGEs accumulate in neurofibrillary tangles and amyloid plaques in AD brains. This research should encourage a more proactive approach to early diagnosis of diabetes and nutritional counseling for AD patients.

PMID: 20030463 [PubMed - indexed for MEDLINE]

PKR, the double stranded RNA-dependent protein kinase as a critical target in Alzheimer's disease.

Morel M, Couturier J, Lafay-Chebassier C, Paccalin M, Page G

PKR, the double stranded RNA-dependent protein kinase as a critical target in Alzheimer's disease.

J Cell Mol Med. 2009 Aug;13(8A):1476-88

Authors: Morel M, Couturier J, Lafay-Chebassier C, Paccalin M, Page G

Amyloid beta-peptide (Abeta) deposits and neurofibrillary tangles are key hallmarks in Alzheimer's disease (AD). Abeta stimulates many signal transducers involved in the neuronal death. However, many mechanisms remain to be elucidated because no definitive therapy of AD exists. Some studies have focused on the control of translation which involves eIF2 and eIF4E, main eukaryotic factors of initiation. The availability of these factors depends on the activation of the double-stranded RNA-dependent protein kinase (PKR) and the mammalian target of rapamycin (mTOR), respectively. mTOR positively regulates the translation while PKR results in a protein synthesis shutdown. Many studies demonstrated that the PKR signalling pathway is up-regulated in cellular and animal models of AD and in the brain of AD patients. Interestingly, our results showed that phosphorylated PKR and eIF2alpha levels were significantly increased in lymphocytes of AD patients. These modifications were significantly correlated with cognitive and memory test scores performed in AD patients. On the contrary, the mTOR signalling pathway is down-regulated in cellular and animal models of AD. Recently, we showed that p53, regulated protein in development and DNA damage response 1 and tuberous sclerosis complex 2 could represent molecular links between PKR and mTOR signalling pathways. PKR could be an early biomarker of the neuronal death and a critical target for a therapeutic programme in AD.

PMID: 19602051 [PubMed - indexed for MEDLINE]