Current Drug Targets - CNS & Neurological Disorders, 2005, 4, 383-403 383 Alzheimer’s Disease-Associated Neurotoxic Mechanisms and Neuroprotective Strategies C. Pereira + , P. Agostinho + , P.I. Moreira, S.M. Cardoso and C.R. Oliveira* Center for Neuroscience and Cell Biology and Institute of Biochemistry, Faculty of Medicine of Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal Abstract : The characteristic hallmarks of Alzheimer’s disease (AD), the most common form of dementia in the elderly, include senile plaques, mainly composed of beta-amyloid (Aβ) peptide, neurofibrillary tangles and selective synaptic and neuronal loss in brain regions involved in learning and memory. Genetic studies, together with the demonstration of Aβ neurotoxicity, led to the development of the amyloid cascade hypothesis to explain the AD-associated neurodegenerative process. However, a modified version of this hypothesis has emerged, the Aβ cascade hypothesis, which takes into account the fact that soluble oligomeric forms and protofibrils of Aβ and its intraneuronal accumulation also play a key role in the pathogenesis of the disease. Recent evidence posit that synaptic dysfunction triggered by non fibrillar Aβ species is an early event involved in memory decline in AD. The current understanding of the molecular mechanisms responsible for impaired synaptic function and cognitive deficits is outlined in this review, focusing on oxidative stress and disturbed metal ion homeostasis, Ca 2+ dysregulation, mitochondria and endoplasmic reticulum dysfunction, cholesterol dyshomeostasis and impaired neurotransmission. The activation of apoptotic cell death as a mechanism of neuronal loss in AD, and the prominent role of neuroinflammation in this neurodegenerative disorder, are also reviewed herein. Furthermore, we will focus on the more relevant therapeutical strategies currently used, namely those involving antioxidants, drugs for neurotransmission improvement, hormonal replacement, γ- and β- secretase inhibitors, Aβ clearance agents (Aβ immunization, disruption of Aβ fibrils, modulation of the cholesterol-mediated Aβ transport), non- steroidal anti-inflammatory drugs (NSAIDs), microtubules stabilizing drugs and kinase inhibitors. Keywords: Beta-amyloid, tau, neuroinflammation, synaptic dysfunction, oxidative stress, neurotransmission, cholesterol, therapeutics. 1. INTRODUCTION 1.1. Neuropathological Hallmarks Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. The risk of AD dramatically increases with aging, affecting 7-10% of individuals over age 65, and about 40% of persons over 80 years of age, and it is predicted that the incidence of AD will increase threefold within the next 50 years if no therapy intervenes [1]. In developed societies where life expectancy has been considerably extended, this devastating disease actually represents a major public health concern, being estimated that 22 million people worldwide will develop this progressive neurodegenerative disorder by 2025 [2]. AD is characterized clinically by global cognitive dysfunction, especially memory loss, behavior and personality changes, and impairments in the performance of activities of daily living that leaves end-stage patients bedridden, incontinent and dependent on custodial care. Patient’s death occurs on average, 9 years after diagnosis. Despite the strong progresses made in AD research in the last decades, no treatment with a strong disease-modifying effect is currently available. The neuropathological hallmarks of AD are neuritic (senile) plaques, which are extracellular deposits predominantly composed of fibrillar beta-amyloid (Aβ) peptide, usually surrounded by reactive astrocytes, activated microglia and dystrophic neurites (altered axons and dendrites), and intracellular neurofibrillary tangles (NFT) composed of filamentous aggregates called paired helical filaments (PHF) of hyperphosphorylated protein tau, frequently conjugated to ubiquitin [3]. These histopathological lesions, prerequisites for a confirmed clinical diagnosis of AD after death, are restricted to selective regions, particularly the hippocampus, a centre for memory, and the cerebral cortex, which is involved in reasoning, memory, language and other important thought processes. These brain regions are reduced in size in AD patients as the result of degeneration of synapses and death of neurons. Most cases of AD are sporadic, and probably result from the synergistic action of genetic and environmental factors. Advanced age and inheritance of the ε 4 allele of the polymorphic apolipoprotein E gene (APOE) are the major risk factors, although neither is sufficient to cause the disease. A small percentage of cases, referred as familiar AD, are inherited in an autosomal dominant fashion (reviewed in [4]). Sporadic and familiar cases of the disease are pathologically and clinically indistinguishable, but the familiar forms generally have an earlier age of onset. *Address correspondence to the author at the Center for Neuroscience and Cell Biology and Institute of Biochemistry, Faculty of Medicine of Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal; Tel: 351- 239-820190; Fax: 351- 239-822776; E-mail: catarina@cnc.cj.uc.pt + The authors contributed equally to this review. 1568-007X/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.