Major characteristics of Alzheimer's disease (AD) are synaptic loss, cholinergic dysfunction, and abnormal protein depositions in the brain. The amyloid ␤-peptide (A␤), a proteolytic fragment of amyloid ␤ precursor protein (APP), aggregates to form neuritic plaques and has a causative role in AD. A present focus of AD research is to develop safe A␤-lowering drugs. A selective acetylcholinesterase inhibitor, phenserine, in current human trials lowers both APP and A␤. Phenserine is dose-limited in animals by its cholinergic actions; its cholinergically inactive enantiomer, posiphen (ϩ)-[phenserine], was assessed. In cultured human neuroblastoma cells, posiphen, like phenserine, dose-and time-dependently lowered APP and A␤ levels by reducing the APP synthesis rate. This action translated to an in vivo system. Posiphen administration to mice (7.5-75 mg/kg daily, 21 consecutive days) significantly decreased levels of total APP (tissue mass-adjusted) in a dose-dependent manner. A␤ 40 and A␤ 42 levels were significantly lowered by posiphen (Ն15 mg/kg) compared with controls. The activities of ␣-, ␤-, and ␥-secretases were assessed in the same brain samples, and ␤-secretase activity was significantly reduced. Posiphen, like phenserine, can lower A␤ via multiple mechanisms and represents an interesting drug candidate for AD treatment.Alzheimer's disease (AD) is typified by progressive impairment in short-term memory and emotional disturbances that result from dysfunction and death of neurons in the hippocampus and associated regions of the limbic system and cerebral cortex. These aberrations are considered to result, in part, from microtubule-associated protein () tangles and abnormal aggregates of cytoskeletal proteins (Cairns et al., 2004), oxidative stress, and the overproduction and accumulation of amyloid-␤ peptide (A␤) in and surrounding neurons (Selkoe, 2005).This 39-to 43-amino acid peptide (molecular mass ϳ4.1 kDa) is a core constituent of amyloid plaques and results from two catalytic cleavages of the larger integral membrane protein, amyloid-␤ precursor protein (APP; ϳ110 -130 kDa), at the N terminus (␤-secretase) and C terminus (␥-secretase) of A␤ (Sambamurti et al., 2002;Lahiri et al., 2003b;Selkoe, 2005). Significant evidence indicates that A␤ changes conformation from a physiological to a pathological, fibrillar peptide form, which not only induces local structural disruption of synapses and neurite breakage but also results in cell death due to perturbed calcium homeostasis and oxidative stress. In addition, soluble aggregates of A␤ or A␤-derived diffusible ligands found in the brains of AD patients have been recently shown to target synapses (Gong et al., 2003) and play a role in inhibiting LTP (Walsh et al., 2002;LaFerla and Oddo, 2005). Conjointly, these studies point to the importance of A␤ in learning and memory, suggest a causative role of A␤ in AD pathophysiology, and thereby support its

Memantine is a moderate-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that stabilizes cognitive, functional, and behavioral decline in patients with moderate to severe Alzheimer's disease (AD). In AD, the extracellular deposition of fibrillogenic amyloid-beta peptides (Aβ) occurs due to aberrant processing of the full-length Aβ precursor protein (APP). Memantine protects neurons from the neurotoxic effects of Aβ and improves cognition in transgenic mice with high brain levels of Aβ. However, it is unknown how memantine protects cells against neurodegeneration and affects APP processing and Aβ production. We report the effects of memantine in three different systems. In human neuroblastoma cells, memantine, at therapeutically relevant concentrations (1-4 μM), decreased levels of secreted APP and Aβ . Levels of the potentially amylodogenic Aβ 1-42 were undetectable in these cells. In primary rat cortical neuronal cultures, memantine treatment lowered Aβ 1-42 secretion. At the concentrations used, memantine treatment was not toxic to neuroblastoma or primary cultures and increased cell viability and/or metabolic activity under certain conditions. In APP/presenilin-1 (PS1) transgenic mice exhibiting high brain levels of Aβ 1-42 , oral dosing of memantine (20 mg/kg/day for 8 days) produced plasma drug concentration of 0.96 μM and significantly reduced the cortical levels of soluble Aβ . The ratio of Aβ 1-40 /Aβ 1-42 increased in treated mice, suggesting effects on the γ-secretase complex. Thus, memantine reduces the levels of Aβ peptides at therapeutic concentrations and may inhibit the accumulation of fibrillogenic Aβ in mammalian brains. Memantine's ability to preserve neuronal cells against neurodegeneration, increase metabolic activity, and lower Aβ level has therapeutic implications for neurodegenerative disorders. KeywordsAging; cortex; dementia; lysosome; membrane; tissue culture; memory In Alzheimer's disease (AD), a gradual impairment in short-term memory and cognition results from the dysfunction and death of neurons in the hippocampus, limbic system, and cerebral cortex (Goedert and Spillantini, 2006;Tanzi and Bertram, 2008). AD is characterized by brain * Contributed equally ** Corresponding author: Debomoy K. Lahiri, PhD, Department of Psychiatry, Indiana University School of Medicine, 791 Union Drive, Indianapolis, USA, Tel: (317) 274-2706; Fax: (317) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript depositions of amyloid plaques and neurofibrillary tangles, loss of the synaptophysin protein, and deficits in cholinergic neurotransmission (Giacobini, 2003;Lahiri et al., 2003;Reinhard et al., 2005;Selkoe, 2005). These aberrations are believed to result, in part, from oxidative stress, membrane damage, and the over-production and accumulation of amyloid-β peptide (Aβ), a 39-43 amino acid polypeptide that is a core constituent of amyloid plaques (Dumery et al., 2001;Sambamurti et al., 2006). Two Aβ peptides predominate in brain tissue, one i...

Inflammatory and oxidative events are up-regulated in the brain of AD patients. It has been reported that in animal models of AD, exposure to aluminum (Al) or copper (Cu) enhanced oxidative events and accumulation of amyloid beta (Ah) peptides. The present study was designed to evaluate the effect of a 3-month exposure of mice to copper sulfate (8 AM), aluminum lactate (10 or 100 AM), or a combination of the salts. Results suggest that although Al or Cu may independently initiate inflammatory or oxidative events, they may function cooperatively to increase APP levels. D

The aging brain shows selective neurochemical changes involving several neural cell populations. Increased brain metal levels have been associated with normal aging and a variety of diseases, including Alzheimer's disease (AD). Melatonin levels are decreased in aging, particularly in AD subjects. The loss of melatonin, which is synthesized by the pineal gland, together with the degeneration of cholinergic neurons of the basal forebrain and the deposition of aggregated proteins, such as the amyloid beta peptides (Abeta), are believed to contribute to the development of cognitive symptoms of dementia. Aging and its variants, such as AD, should be viewed as the result of multiple "hits," including alterations in the levels of Abeta, metals, cholinesterase enzymes, and neuronal gene expression. Herein, we present evidence in support of this theory, based on several studies. We discuss melatonin's neuroprotective function, which plays an important role in aging, prolongation of life span, and health in the aged individual. It interacts with metals and, in some cases, neutralizes their toxic effects. Dietary supplementation of melatonin restores its age-related loss. In mice, an elevated brain melatonin significantly reduced levels of potentially toxic Abeta peptides. Thus, compensation of melatonin loss in aging by dietary supplementation could well be beneficial in terms of reducing metal-induced toxicity, lipid peroxidation, and losses in cholinergic signaling. We propose that certain cholinesterase inhibitors and the NMDA partial antagonist memantine, which are FDA-approved drugs for AD and useful to boost central nervous system functioning, can be made more effective by their combination with melatonin or other neuroprotectants. Herein, we highlight studies elucidating the role of the amyloid pathway, metals, melatonin, and the cholinergic system in the context of aging and AD. Finally, melatonin is present in edible plants and walnuts, and consuming foodstuffs containing melatonin would be beneficial by enhancing the antioxidative capacity of the organisms.