Current Topics in Medicinal Chemistry - Volume 2, Issue 4, 2002

Alzheimer's Disease (AD) is a progressive neurodegenerative disease that is prevalent among the elderly. It is a heterogeneous disease involving a number of genetic components, risk factors and other poorly defined elements that all impact on the accumulation of beta-amyloid peptide (Aβ). Current understanding of pathology, biochemistry and genetics strengthens the notion that Aβ is potentially the common pathogenic ag Read More

Over the past decade, considerable effort was focused on the development of muscarinic and nicotinic agonists for the treatment of Alzheimer's disease. The rationale for developing muscarinic agonists was based on the role of acetylcholine in learning and memory function and the consistent neurochemical finding that cholinergic neurons degenerated in Alzheimer's patients. Thus far, the clinical utility of muscarinic Read More

The first proteolytic step in the processing of amyloid precursor protein (APP) to amyloid-beta (Aβ) in the brain is performed by β-site APP cleaving enzyme (BACE1). This enzyme is a membrane bound aspartic protease with high homology of the catalytic domain to renin and pepsin and of yet unknown physiologic function. It is a primary drug discovery target for Alzheimer's disease therapy. The first potent inhibitors are based Read More

The amyloid-β peptide (Aβ) is the major protein component of the characteristic cerebral plaques of Alzheimer's disease (AD), and a large body of evidence supports a pathogenic role for this peptide. Thus, the proteases β- and γ-secretase that are responsible for carving Ab out of its precursor protein are considered prime targets for therapeutic design. β-Secretase is a membrane-anchored aspartyl protease of the pepsin famil Read More

The field of neuroimaging has made several recent advances understanding Alzheimer's disease, a debilitating disease which affects approximately 4 million people in the United States [1]. Despite recent therapeutic advances, available treatments at present are aimed primarily at slowing progression of the disease rather than halting it completely or reversing its progression. Early detection of the disease has, therefore, b Read More

Neurofibrillary tangles (NFTs) are a distinguishing neuropathological feature found in postmortem brains of Alzheimer's disease (AD) and tauopathy patients. The density of these lesions correlates with severity of AD and their distribution follows a characteristic pattern of expansion as the disease progresses. The principle components of NFTs are highly phosphorylated forms of the microtubule-associated protein, tau. Tau p Read More

Amyloid beta peptide (Aβ) is implicated in the pathogenesis of Alzheimer's disease (AD), particularly as oligomers or polymers that are correlated with Ab cellular toxicity. Inhibition of the formation of toxic forms of Aβ has therefore emerged as one approach to the treatment of AD. This article reviews efforts to adapt the structure of Aβto the design and testing of peptide-based inhibitors of Aβ polymerization of interest as poten Read More