Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents - Volume 3, Issue 1, 2003

Cerebral accumulation of Amyloid β (Aβ) peptides is an early event in establishing Alzheimer's disease pathology. Based on epidemiological studies pointing to a link between cholesterol metabolism and Alzheimer's disease (AD) as well as experimental evidence implicating cholesterol in the process of Aβ production and accumulation it is now believed that cholesterol-lowering therapies will be of value for AD prevention and / or treatment. Epidemiological studies have revealed that the use of statins for the treatment of hypercholesterolemia- and hyperlipidemia-related, coronary arterial disease is associated with a decreased prevalence or a decreased risk of developing AD. It is therefore necessary to test statins in one or more animal models of AD in order to establish which disease features are affected by statin treatment, the relative efficacy with which different statins modify these features and the mechanism(s) by which statins affect AD phenotypes. Here we discuss the results of a preclinical study aimed at determining the effects of atorvastatin (Lipitor-R) on brain Aβ deposition in the PSAPP transgenic mouse model of Alzheimer's disease. The atorvastatininduced hypocholesterolemia was associated with a marked reduction in brain Aβ deposition and was also accompanied with a reduction in brain ApoE content. Based on our findings and the observations of others regarding the effects of statins on Aβ metabolism and taking into account the current knowledge of the various activities of statins, we propose a working hypothesis of the mechanisms by which statins modulate brain amyloidosis.

The brain is an organ which is at once enriched in transition metals and highly susceptible to oxidative stress. By virtue of its high affinity for copper the Alzheimer's amyloid protein (Aβ) is capable of catalytic generation of neurotoxic H2O2 while its aggregation and deposition are zinc-dependent. These properties are exaggerated by conditions present in the aging brain. Amyloid from human brain specimens can be solubilized by the application of selected Cu / Zn chelators thus demonstrating the role of metals in amyloid architecture. Similarly, the toxicity of the metal / Aβ complex is ameliorated by metal complexing agents. Clioquinol, a bioavailable Cu / Zn chelator has been successfully used to inhibit amyloid deposition in a transgenic animal model for Alzheimer's disease and is presently undergoing human efficacy trials.

Alzheimer's disease (AD) is believed to involve increased soluble but toxic beta amyloid (Aβ) peptide aggregates, leading to the accumulation of insoluble Aβ deposits, inflammation, oxidative damage, tau pathology and ultimately cognitive deficits. Blocking Aβ formation early should prevent AD, but most interventions are likely to occur after seeding of deposits and tangles and after initiation of the amyloid cascade. In order to identify agents that might suppress both amyloid and the response to amyloid in vivo, we infused toxic soluble Aβ into rat ventricles and screened agents targeting amyloid, oxidative damage and inflammation. The combined NSAID / antioxidant curcumin was found to be most efficacious in reducing amyloid, oxidative damage, inflammation and synaptic marker loss. Similar curcumin benefits were then shown in APPsw transgenic mice. One central mechanism underlying curcumin's reductions in soluble and guanidine-extracted insoluble Aβ appears to be stimulation of phagocytic clearance pathways. Curcumin stimulates amyloid phagocytosis and clearance while exerting net anti-inflammatory activity. Because curcumin and its derivatives (curcuminoids) also protect against the response to amyloid, particularly the oxidative damage and resulting synaptic loss, they appear well suited for AD treatment. Evidence also supports curcumin effects on reducing Aβ aggregation and lowering cholesterol. Low cost, low dose efficacy, low toxicity and multiple potential protective activities make curcumin and its derivatives strong candidates for AD prevention.

One increasingly dominant hypothesis regarding the pathogenesis of Alzheimer dementia is the inflammation hypothesis. In brief, this hypothesis argues that at least some of the neurodegeneration found in this disease is secondary to excessive activation of microglia and astrocytes, resulting in secretion of pro-inflammatory mediators, activation of the complement cascade and degeneration of synapses and neurons. The APP+PS1 transgenic mouse is a model of Aβ amyloid deposition that results in a phenotype resembling some but not all aspects of Alzheimer's. Our group has evaluated a number of manipulations designed to both exacerbate and ameliorate the microglial activation in this transgenic model, ranging from LPS injections, administration of anti-Aβ antibodies and treatment with antiinflammatory drugs. Contrary to our original predictions that microglial activation should exacerbate the Alzheimer phenotype in these mice, we find that treatments that cause microglial activation are associated with reduced amyloid loads. These data are discussed in the context of differences between the murine and human immune systems and qualitative differences in the Aβ deposits found in these mouse models compared to human specimens.

Many of the recent advances in AD stem from the study of a 40-42 amino acid peptide called the amyloid beta protein (Aβ), as the essential pathologic marker of the disorder [1-2]. Our studies and those of others have shown that Aβ is central to the process of neurodegeneration in AD by initiating the production of partially reduced oxygen species and damaging essential macromolecules in the CNS. A growing body of literature links these destructive oxidative processes with some neurodegenerative aspects of AD. Herein we discuss the evidence that melatonin and related indoles can be use as potential therapeutic agents in Alzheimer's disease (AD). The principal findings related to the free radical scavenging and antioxidative properties of melatonin in various paradigms of AD are presented. The hormone efficacy and the likely mechanisms involved in its ability to reduce neuronal damage mediated by oxygen-based reactive species in AD models of neurodegeneration are discussed. We will discuss the experimental data suggesting that besides the direct scavenging properties and indirect antioxidant actions of melatonin, its ability to protect neurons probably also stems from novel antiamyloidogenic properties of the hormone. Melatonin is also unique because of the ease with which it passes through the blood-brain barrier and has distinct physiological relationships to the aging process.A brief introductory discussion on the biology and neuropathology of AD is offered with a consideration of the relationship between free radicals and the pathogenesis of the disease.

A large (and still growing) body of evidence suggests that the β-amyloid peptide (Aβ) is central to the pathophysiology of Alzheimer's Disease (AD) and may in fact initiate disease processes that lead to this intractable neurodegenerative disorder. Amyloid plaques composed of Aβ progressively develop in the brains of AD patients, and mutations in three genes (amyloid precursor protein, presenilin1, presenilin2) cause early on-set familial AD by increasing synthesis of the toxic Aβ42 peptide. Given the strong correlation between Aβ and AD, therapeutic strategies to lower Aβ levels in the brain should prove beneficial for the treatment of AD. Aβ is derived from the amyloid precursor protein via cleavage by two proteases, β- and γ-secretase. β-secretase was identified as the novel aspartic protease BACE1, and it initiates the formation of Aβ. Consequently, BACE1 in principle is an excellent therapeutic target for reducing the production of Aβ in AD. However, the discovery of the homologue BACE2 raised the question of whether it too may be a β-secretase. To settle this issue, our group and others have used gene targeting to generate BACE1 deficient (knockout) mice. These BACE1 knockout mice have been instrumental in validating BACE1 as the authentic β-secretase in vivo . Here, I review the recent studies of the BACE1 knockouts and discuss the implications of these studies for therapeutic approaches that target BACE1 for the treatment of AD.

Transgenic βAPP mice are valid and useful models of Alzheimer's disease (AD) as they effectively recreate Aβ deposition, which is widely regarded as the central pathogenic event in the disease. Transgenic mice do not, however, replicate the initial pathogenic event of the most common form of AD. The majority of AD is not caused by any of the gene mutations employed to create these mice. As cortical Aβ deposition is a common, if not universal, occurrence in many mammalian species, its cause is likely to lie within the physiologic process of aging. We have created an animal model of Aβ deposition by inducing cortical cholinergic deafferentation, a well-known aging change, in the brains of young rabbits. Lesioning the cholinergic nucleus basalis magnocellularis (nbm) results in cortical cholinergic deafferentation and cortical Aβdeposition. The Aβ deposits are primarily vascular, with occasional perivascular plaques. The specificity of this change for cholinergic processes has been demonstrated by the reduction of lesion-induced Aβ deposition by cholinergic therapy with AF267B, an m1-selective muscarinic agonist, and physostigmine, an acetylcholinesterase inhibitor, and by showing that lesioning of the noradrenergic locus ceruleus does not cause Aβ deposition. Significant decreases in cortical synaptic antigen density occur at 6 months post-lesion. Examination of longer survival periods has been complicated by regeneration of cortical cholinergic afferents but repetitive nbm lesions are expected to overcome this obstacle. Agerelated degeneration of the nbm in humans may be a major contributor to Aβ deposition in normal aging and AD.

We examine the evolution of the discovery of peripheral cholinergic changes in Alzheimer's disease (AD). Further, we demonstrate a significant eccrine sudomotor cholinergic dysfunction after intradermal injection of pilocarpine in AD subjects compared to non-demented-non-neuropathic control subjects. Active sudomotor gland density was quantified following pilocarpine injection and thermal stimulation. Sympathetic skin responses were collected on the opposite side of the body. The active sudomotor gland density was significantly lower and the percentage of tested skin surface without pilocarpine-activated sweat glands was significantly greater in AD patients after pilocarpine stimulation. The degree of sudomotor activity loss was correlated directly with cognitive decline in AD patients. Neither eccrine gland loss nor afferent or preganglionic neuron dysfunction accounted for these differences. Our experiments reveal sudomotor activity is affected at the postganglionic sympathetic neuron level in AD, thereby inducing readily observable clinical manifestations sufficient to distinguish AD patients from non-demented individuals.

AβPP transgenic mice replicate some aspects of Alzheimer's disease pathology. Despite some similarities, significant biochemical and physical differences exist between the amyloid deposits characteristic of transgenic animals and AD patients. These differences may account for the fact that the promising results obtained by amyloid vaccination of AβPP transgenic mice were not replicated in humans. Aβ is an evolutionarily-conserved molecule of unknown function. Future therapeutic strategies directed toward interfering with amyloid production should be implemented with caution.