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Neurodegenerative Disease Alzheimer’s Disease Current State of the Art in Preclinical Research in Alzheimer’s Disease – A Focus on Mode of Action in Pharmacological and Non-pharmacological Approaches Kiren Ubhi 1 and Eliezer Masliah 2 1. Postgraduate Research Fellow, Department of Neurosciences; 2. Professor of Neuroscience and Pathology, Departments of Neurosciences and Pathology, University of California, San Diego, La Jolla, California, US Abstract Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterised by progressive memory deficits and other cognitive disturbances. Neuropathologically, AD is characterised by synaptic deficits, progressive loss of neocortical, limbic and basal forebrain cholinergic neurons and the abnormal extracellular accumulation of amyloid-beta (Aβ) and the intracellular aggregation of the cytoskeletal protein tau. Currently available AD therapies either only temporarily delay disease progression or address the symptoms but are unable to alter the underlying mechanisms of disease. Therefore, ongoing AD research is focused at better understanding pathogenesis and at developing disease-modifying experimental therapeutic approaches. This review will summarise the main areas of preclinical research for AD therapeutics that includes those aimed at modulating the processing of amyloid precursor protein (APP) and the production of Aβ; ameliorating the pathological accumulation of Aβ or tau; augmenting neuroprotective activities in the AD brain; and augmenting neurorestoration in the AD brain. The review will also discuss a novel multimodal therapeutic approach to AD using Cerebrolysin, a peptidergic mixture with neurotrophic-like effects. Keywords Neurotrophic factors, synapses, ageing, neurodegeneration, Cerebrolysin Disclosure: The authors are consultants to EVER Neuro Pharma. Received: 19 September 2012 Accepted: 5 November 2012 Citation: European Neurological Review, 2012;7(4):216–23 Correspondence: Eliezer Masliah, Departments of Neurosciences and Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0624, US. E: emasliah@ucsd.edu Support: The publication of this article was funded by EVER Neuro Pharma GmbH. The views and opinions expressed are those of the authors and not necessarily those of EVER Neuro Pharma GmbH. Alzheimer’s disease (AD) is the seventh most prevalent cause of death in the US and is the leading cause of dementia, affecting more than 5 million Americans and 26 million people worldwide. Without an effective therapy it is estimated that the number of patients with AD will double by the year 2050. 1 Cognitive impairment in patients with AD is closely associated with loss of synapses and the formation of neurofibrillary tangles (NFT) in the neocortex and limbic system. 2–6 The two major neuropathological findings in patients with AD are extracellular plaques formed mainly of the amyloid-beta (Aβ) peptide, 7–9 and intracellular NFT, containing hyperphosphorylated tau. 10–12 Several lines of investigation support the view that increasing levels of Aβ 1–42 , the proteolytic product of amyloid precursor protein (APP) metabolism, might be centrally involved in the pathogenesis of AD 7–9,13 and it has been proposed that in AD, progressive accumulation of Aβ might be involved in the mechanisms underlying NFT formation and synaptic loss. 14–17 More specifically in recent years the potential role of neurotoxic Aβ oligomers has emerged as a topic of considerable interest. 18–21 AD medications currently prescribed are aimed at individuals with mild to moderate AD and include drugs such as donepezil, rivastigmine and 216 galantamine, all of which are acetylcholinesterase inhibitors and work by preventing the breakdown of acetylcholine and stimulating nicotinic receptors to release acetylcholine in the brain. Memantine, another drug currently approved for use in moderate to severe AD, is an N-methyl-D-aspartate (NMDA) receptor antagonist and acts on the glutamatergic system by blocking the toxic effects associated with excess glutamate, thereby regulating glutamate activation. In addition to its activity at the NMDA receptor, memantine also acts as a non-competitive antagonist at the 5-hydroxytryptamine (5-HT) serotonin and nicotinic receptors. Although each of these drugs has demonstrated treatment effects on the cognitive, functional and behavioural problems commonly associated with AD, these drugs simply slow the progression of AD but do nothing to tackle the underlying pathogenesis. In this context, there has been real interest in elucidating the main pathways involved in AD pathogenesis and developing therapies acting on these key pathways. This review will focus on preclinical experimental therapies being investigated for AD, with particular focus on the role of multimodal therapies, typified by Cerebrolysin (CBL), a peptide mixture with neurotrophic-like effects. © TOUCH MEDICAL MEDIA 2012