The development of Alzheimer's disease is dependent on the aberrant processing of normal proteins in the neuronal cell, as shown above. The presenilins are transmembrane proteins that contain peptidase activity, and that span the membrane 8 times. There are two forms of presenilin, termed presenilin 1 (PS1, a 467 amino acid protein derived from chromosome 14) and presenilin 2 (PS2, a 448 amino acid protein derived from chromosome 1). Both of these proteins occur ubiquitously in neurons, and act as the catalytic subunit of gamma-secretase. Chromosome 21 codes for a third protein that is crucial for the development of Alzheimer's disease, known as amyloid precursor protein (APP). The function of APP is not fully understood. APP is normally processed by several proteases, the most important of which are alpha-secretase, beta-secretase (BACE) and gamma-secretase. The cleavage sites on APP are shown below:
Under normal conditions, APP can be hydrolyzed by alpha-secretase, as shown in the picture below, resulting in an inactive, harmless peptide. more often, however, APP is cleaved in a two-step process: beta-secretase cleaves APP at an aspartate residue near the N-terminus, as shown in the picture below, and then the gamma-secretase activity of presenilin cleaves APP in the membrane-bound region, producing a 40 amino acid peptide known as A-beta40 or beta-amyloid 40. As shown below, there are a number of potential mutations that can occur in the presenilins that result in abnormal cleavage of APP (the so-called amyloid hypothesis).
When these mutation occur, APP is processed to a 42 amino acid beta-amyloid protein known as A-beta42 or beta-amyloid 42. This form of amyloid protein is more "sticky" than the 40 amino acid version, and is prone to form diffuse plaques (see below). Neuronal injury results in the recruitment of kinases that hyperphosphorylate tau proteins, and these combine with A-beta42 to form neurofibrillary tangles that are characteristic of the disease. The resulting neuronal damage results in widespread cell death, and ultimately in the dementia observed in Alzheimer's patients.
Drug Targets in Alzheimers.
Currently available treatments for Alzheimer's disease include agents that treat the symptoms of the disease without addressing the biochemical etiology. A second theory regarding the etiology of Alzheimer's is known as the cholinergic hypothesis. A deficit in central cholinergic transmission caused by degeneration of the basal forebrain nuclei is an important pathological and neurochemical feature of AD. A progressive loss of nicotinic receptors over the disease course of AD has also been described, and there is evidence of a role for these receptors in the deficits in memory and cognition.Thus acetylcholinesterase inhibitors that act centrally are of value in treatment. During the neurodegeneration caused by Alzheimer's, an increase in extracellular glutamate is thought to lead to excessive activation of NMDA receptors with consequent intracellular accumulation of Ca2+. This intracellular accumulation of calcium then initiates a cascade of events that results in further neuronal death. NMDA antagonists could potentially protect neurons from glutamate-mediated toxicity without preventing physiological activation of the NMDA receptor.
Current Alzheimer's research in medicinal chemistry is aimed at the identification of agents that effect the underlying biochemical causes of Alzheimers. Thus the enzymes gamma-secretase and BACE have become highly desirable targets for specific inhibitors, with the goal of reducing the abnormal processing of APP, and thus the reduction of plaque and tangle formation.
Acetylcholinesterase Inhibitors.
Acetylcholinesterase inhibitors have beneficial effects on cognitive, functional, and behavioural symptoms of Alzheimer's. Tacrine, donepezil, and galantamine selectively inhibit acetylcholinesterase. Galantamine also improves cholinergic neurotransmission by acting as an allosteric ligand at nicotinic acetylcholine receptors to increase presynaptic acetylcholine release and postsynaptic neurotransmission.In addition to the inhibition of acetylcholinesterase, rivastigmine inhibits butyrylcholinesterase, which is about 10% of the total cholinesterase in normal human brains and mainly associated with glial cells. Over the course of Alzheimer's, acetylcholinesterase activity decreases while butyrylcholinesterase activity stabilizes and even increases, probably in relation to glial proliferation; there is also a reported change in the ratio of acetylcholinesterase to butyrylcholinesterase.Butyrylcholinesterase may act as a compensatory mechanism for acetylcholine metabolism and support the potential of butyrylcholinesterase as a suitable target for the treatment of AD.Although donepezil, rivastigmine, and galantamine are part of the same therapeutic class, they differ in their pharmacology and pharmacokinetics.
Memantine.
A dysfunction of glutamatergic neurotransmission, manifested as neuronal excitotoxicity, is involved in the etiology of Alzheimer's disease. Targeting the glutamatergic system, specifically NMDA receptors, offers a novel approach to treatment in view of the limited efficacy of existing drugs targeting the cholinergic system. Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors. By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions which forms the basis of neuronal excitotoxicity. The low-affinity of memantine, however, preserves the physiological function of the receptor as it can still be activated by the relatively high concentrations of glutamate released following depolarisation of the presynaptic neuron.Memantine also acts as an uncompetitive antagonist at the 5HT3 receptor, and as an uncompetetive antagonist at different neuronal nicotinic neuronal receptors (nAChRs) at potencies simular to the NMDA receptor, although it's effects at these loci are not well understood.
BACE and Gamma-Secretase Inhibitors.
As was outlined above, the aspartyl proteases BACE and gamma secretase are inviting targets for drug discovery. A number of inhibitors are advancing to clinical trials that are transition state analogues of the BACE reaction, which is shown below. As you can see, the cleavage of the bond between a leucine and an aspartate (see above) by BACE generates the amino terminus of APP. Because the aspartyl protease reaction is a hydrolysis, the transition state is tetrahedral, and thus transition state inhibitors must mimic this transition state in order to bind with high affinity.
Transition state inhibitors for aspartyl proteases often include transition state isosteres, the most common of which are statine and hydroxyethylamine. Of course, stereochemistry is a critical component of the drug design process, since only one isomer will have high affinity for the enzyme.
An example of a BACE inhibitor, of which there are now hundreds, appears below. Less is known about gamma secretase, but inhibitors of this enzyme have also been developed, and some have advanced to clinical trials.
Gamma secretase inhibitors are often less complex, but still contain the transition state core:
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