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 agent in an apparent convergence of various mechanisms leading to the decline of cognitive function and neuronal loss. While many issues remain controversial, recent evidence attributing Aβ accumulation to cognitive decline in humans, coupled to the demonstrated improvement of cognitive function following Aβ immunization in pre-clinical models, strongly supports the ”amyloid hypothesis“ and a central role for Aβ in the pathophysiology and etiology of AD. These and other observations endorse the notion that therapeutic strategies targeting the inhibition of Aβaccumulation by the use of protease inhibitors, immunization or other strategies, may provide disease-altering interventions to the development and progression of AD. The only approved and marketed treatments currently available for AD are the acetylcholinesterase inhibitors, a palliative strategy aimed at the temporary improvement of cognitive function. The purpose of this overview is to provide a brief understanding of key events leading to the progression of AD and to highlight a few of the current and most promising therapeutic strategies that one day might be available for the treatment of AD.

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 agonists remains unproven, yet recent studies suggest that muscarinic agonists might be useful in treating not only memory deficits, but also psychiatric disturbances and some of the underlying causes of Alzheimer's disease, such as the deposition of Aβ. In addition, nicotinic receptors may play a role in cognitive function and help regulate the toxicity of amyloid precursor protein. Ultimately, cholinergic agonists may prove useful in the treatment of Alzheimer's disease.

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 on the sequence of APP around the β-secretase cleavage site EVNL / DAEF, with the scissile Leu-Asp amide bond being replaced by a hydroxyethylene transition state analogue isostere. In addition, lipophilic sidechains have been incorporated and a crystal structure of such an octapeptidic inhibitor bound in the active site is already available. Recent progress in the field of BACE inhibition is reviewed.

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 family, while γ-secretase is much more complex. γ-Secretase requires presenilin, a multipass membrane protein that is the site of dozens of missense mutations that alter Ab formation and cause hereditary AD. Two conserved aspartates in presenilin are required for γ-secretase activity, and aspartyl protease transition-state analogue inhibitors of γ-secretase bind directly to presenilins, strong evidence that presenilin is the catalytic component of a novel membrane aspartyl protease. γ-Secretase appears to be a multi-component complex of integral membrane proteins, and so far presenilin and a single-pass membrane protein called nicastrin have been identified as members of this complex. A closely similar or identical protease activity is essential for a signaling pathway critical for embryogenesis and hematopoiesis, raising concerns about γ-secretase as a target. The development of potent and selective inhibitors with good pharmacokinetic properties may soon address these concerns.

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, been a major focus of a variety of neuroimaging techniques, including Positron Emission Tomography (PET), functional Magnetic Resonance Imaging (fMRI), and structural MRI. Recently, these techniques have also been found to be useful in monitoring cognitive and pathological progression of the disease, as well as monitoring response to clinical intervention treatment. A methodology review will be included here as well as a critical evaluation of the advantages and disadvantages of the various techniques.

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 phosphorylation is believed to initiate or facilitate dissociation from microtubules leading to microtubule destabilization, decay of cellular transport properties, and cell death. This review summarizes recent data and prevailing views on the roles of protein kinases and phosphatases in the regulation of tau phosphorylation in vitro and in vivo, taking into account data from human neurodegenerative diseases and from transgenic rodent models. Small molecule inhibitors of tau phosphorylation that serve as important research tools and possibly the basis of potential new therapeutics, are also described. Key challenges in developing effective therapeutic agents include identification of the relevant kinase(s) responsible for aberrant tau phosphorylation in AD, synthesis of inhibitors selectively targeting those kinases and establishment of appropriate animal models.

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 potential AD therapeutics.