Oxidative Stress Hypothesis in Alzheimer's Disease

Abstract

The major hurdle in understanding Alzheimer's disease (AD) is a lack of knowledge about the etiology and pathogenesis of selective neuron death. In recent years, considerable data have accrued indicating that the brain in AD is under increased oxidative stress and this may have a role in the pathogenesis of neuron degeneration and death in this disorder. The direct evidence supporting increased oxidative stress in AD is: (1) increased brain Fe, Al, and Hg in AD, capable of stimulating free radical generation; (2) increased lipid peroxidation and decreased polyunsaturated fatty acids in the AD brain, and increased 4-hydroxynonenal, an aldehyde product of lipid peroxidation in AD ventricular fluid; (3) increased protein and DNA oxidation in the AD brain; (4) diminished energy metabolism and decreased cytochrome c oxidase in the brain in AD; (5) advanced glycation end products (AGE), malondialdehyde, carbonyls, peroxynitrite, heme oxygenase-1 and SOD-1 in neurofibrillary tangles and AGE, heme oxygenase-1, SOD-1 in senile plaques; and (6) studies showing that amyloid beta peptide is capable of generating free radicals. Supporting indirect evidence comes from a variety of in vitro studies showing that free radicals are capable of mediating neuron degeneration and death. Overall, these studies indicate that free radicals are possibly involved in the pathogenesis of neuron death in AD. Because tissue injury itself can induce reactive oxygen species (ROS) generation, it is not known whether this is a primary or secondary event. Even if free radical generation is secondary to other initiating causes, they are deleterious and part of a cascade of events that can lead to neuron death, suggesting that therapeutic efforts aimed at removal of ROS or prevention of their formation may be beneficial in AD. © 1997 Elsevier Science Inc.

Introduction

In 1907, Alois Alzheimer, a German psychiatrist and neuropathologist, initially described the clinical and pathological findings of a 51-year-old woman with a 4 $\text{1}\text{2}$ year course of progressive dementia, which subsequently became recognized as a disorder bearing his name.[1]Autopsy of this patient revealed the presence of silver positive neurofibrillary tangles (NFT), severe cerebral cortical neuron loss, and alterations subsequently known as senile plaques (SP). Early pathologists viewed cerebral atherosclerosis as the cause of Alzheimer's disease (AD). The modern era of knowledge about AD began in the 1960s and 1970s with the understanding of the ultrastructure of the cerebral cortical lesions, deficits in specific neurotransmitters, and recognition of AD as a single entity. In the 1980s and 1990s, molecular biological approaches and other new technologies have offered insight into the molecular alterations in AD, and set the stage for potentially understanding the pathogenetic mechanisms in this disorder.

Alzheimer's disease is the most common form of adult onset dementia. A community based study has suggested that approximately 4 million persons in the United States have AD.[2]This study showed that the prevalence of AD is 3% for persons 65–74 years old, 18.7% for those 75–84 years old, and 47.2% for those over 85 years old. It is the fourth or fifth leading cause of death in this country.[3]With the aging of society, it has been estimated that approximately 9 million individuals could develop AD by the year 2040,[4]unless preventative strategies are found.

Clinical criteria for the diagnosis of AD include dementia established by clinical examination and neuropsychological testing, deficits in two or more areas of cognition, progressive worsening of memory and other cognitive functions, no disturbance in consciousness, onset between ages 40 and 90, and absence of systemic disorders or other brain disease to account for the progressive cognitive decline.[5]A diagnostic laboratory test for AD has not been found and AD remains a diagnosis of exclusion. A definitive diagnosis cannot be made without neuropathological confirmation. Two neuropathological criteria are available for the diagnosis of AD.6, 7The major microscopic alterations in AD are SP and NFT formation, selective neuron loss and shrinkage, synapse loss, neuropil thread formation, and amyloid angiopathy. NFT and SP represent an accumulation of intraneuronal and extracellular filamentous protein aggregates. Hyperphosphorylated tau is the major protein in NFT. Amyloid beta peptide (Aβ), derived from the amyloid precursor protein (APP), is the major protein in SP and amyloid angiopathy.

Alzheimer's disease is a multineurotransmitter deficiency disease. The most consistent neurotransmitter alteration in the cerebral cortex in AD is the loss of the cholinergic markers, choline acetyltransferase, and acetylcholinesterase.[8]In addition, there are deficits in serotonin,[9]noradrenaline,[10]somatostatin,[11]and corticotropin-releasing factor.[12]

The most exciting recent findings in AD are in the area of molecular genetics.[13]Mutations in the APP gene on chromosome 21 have been described in a modest number of patients with familial early-onset AD (reviewed in [14]). Corder and colleagues showed that apolipoprotein E-4 (APO E-4) genotype is an important risk factor in late-onset familial and sporadic AD.15, 16Risk of AD increases and the age of onset decreases with the number of APO E-4 alleles. Up to 90% of individuals homozygous for APO E-4 have a chance of developing AD by age 80.[15]It also has been associated with early-onset AD and may influence the age of onset in some families with APP mutations. APO E-2 genotype appears to be somewhat protective for AD.[17]Recently, multiple mutations have been found on gene S182 (Presenilin 1) on chromosome 14 in early-onset familial AD.[18]Thirty-three different mutations have been identified in Presenilin 1 and all but one are missense mutations.[13]Another gene, E5-1 (Presenilin 2) on chromosome 1, was found to contain two missense mutations in patients with early onset familial AD.[19]In the Volga German kindred, a point mutation on gene STM-2 on chromosome 1 was found.[20]The STM-2 gene is 67% homologous to Presenilin 1.

Defining risk factors for AD is important in the eventual prevention of this disorder. Risk factors that have been defined for AD are: age,[2]presence of APO E-4 alleles,15, 16a family history of AD or dementia,[21]head injury,[22]low educational attainment,[23]and low linguistic ability early in life.[24]

The major hurdle in understanding AD is the paucity of knowledge about the etiology and pathogenesis of the disease. Many etiologic/pathogenetic hypotheses have been advanced for AD: genetic defect, slow or latent virus disorder, energy metabolism deficit, altered APP processing, deficiency of neurotrophic factors, glutamate toxicity (excitotoxicity), mitochondrial defect, trace element neurotoxicity, and free radical-induced neuron degeneration or the oxidative stress hypothesis (reviewed in [25]). It is possible that several of these hypotheses, trace element neurotoxicity, excitotoxicity, mitochondrial defect, and oxidative stress, may interact as pathogenetic mechanisms in AD.

Recently, there has been heightened interest in the role of oxidative stress in neurologic disorders. There is evidence that free radicals play a role in cerebral ischemia-reperfusion, head injury, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Down's syndrome (DS), and AD. The central nervous system (CNS) is especially vulnerable to free radical damage as a result of the brain's high oxygen consumption rate, its abundant lipid content, and the relative paucity of antioxidant enzymes compared with other tissues.[26]The appealing feature of the oxidative stress hypothesis for neurodegenerative diseases is that cumulative oxidative damage over time could account for the late life onset and the slowly progressive nature of these disorders.[26]Increased dopamine turnover, decreased glutathione levels, elevated iron levels, and increased lipid peroxidation in the substantia nigra support the oxidative stress hypothesis in PD.27, 28, 29In ALS, multiple mutations in the copper/zinc (Cu/Zn) superoxide dismutase (SOD-1) gene on chromosome 21 were found in a subset of patients with the familial form of the disease.[30]Transgenic mice overexpressing mutated SOD-1 show only motor neuron degeneration.31, 32Two of the SOD-1 mutant enzymes associated with familial ALS cause the oxidation of a model substrate (spin trap 5,5′-dimethyl-1-pyrroline N-oxide) by H₂O₂ at a higher rate than the wild-type enzyme.[33]These observations suggest that oxidative reactions catalyzed by mutated SOD-1 can lead to specific neuron degeneration. These findings coupled with studies showing an elevation of iron and selenium levels, and glutathione peroxidase activity in the spinal cord in motor neuron disease patients, strongly suggest that free radical mediated injury of anterior horn cells may be involved in the pathogenesis of ALS.34, 35Evidence supporting the oxidative stress hypothesis for AD follows.