Alzheimer's Disease: Synaptic Dysfunction and a ² Molecular Neurodegeneration Alzheimer's Disease: Synaptic Dysfunction and Aβ

Synapse loss is an early and invariant feature of Alzheimer's disease (AD) and there is a strong correlation between the extent of synapse loss and the severity of dementia. Accordingly, it has been proposed that synapse loss underlies the memory impairment evident in the early phase of AD and that since plasticity is important for neuronal viability, persistent disruption of plasticity may account for the frank cell loss typical of later phases of the disease. Extensive multi-disciplinary research has implicated the amyloid β-protein (Aβ) in the aetiology of AD and here we review the evidence that non-fibrillar soluble forms of Aβ are mediators of synaptic compromise. We also discuss the possible mechanisms of Aβ synaptotoxicity and potential targets for therapeutic intervention. Introduction Alzheimer's disease (AD) is an irreversible, progressive brain disorder that slowly destroys memory and cognitive skills. It is the most common human dementia and as such confers a huge emotional and economic burden on patients, caregivers and society [1]. Age is the most significant risk factor, with the chance for developing AD doubling every five years after 65 [2,3]. However, the disease can also strike in mid-life and so-called early-onset AD (EOAD) is designated as dementia developing before 65 years old. Fortunately EOAD is rare with an estimated incidence of 4.2 per 100,000 persons in the 45-64 year age group [4]. The cognitive and pathological changes evident in EOAD and late onset AD (LOAD) are highly similar with the former apparently an accelerated form of the more common LOAD. Because many EOAD cases have a strong Mendelian inheritance pattern they have proved instructive in identifying key gene products involved in the disease process. Specifically, autosomal dominant mutations identified in familial AD all appear to converge on altering the processing of the amyloid precursor protein (APP) [5]. The precise onset of clinical AD is difficult to discern but is often manifested as subtle and intermittent deficits in episodic memory. After many months of gradually progressive impairment of first declarative and then also nondeclarative memory, other cognitive symptoms appear and slowly advance. Over a further period of years a profound dementia develops that affects multiple cognitive and behavioral spheres [6]. Pathologically, the Alzheimer brain is characterized by atrophy and microscopically there are decreases in the numbers of neuronal cell bodies in the limbic and association cortices and in certain subcortical nuclei [7-9] and numerous amyloid plaques and neurofibrillary tangles litter the cerebrum [10-12]. Many studies have examined the relationship between cognitive impairment and plaque and tangle counts and while, in Published: 23 November 2009 Molecular Neurodegeneration 2009, 4:48 doi:10.1186/1750-1326-4-48 Received: 8 August 2009 Accepted: 23 November 2009 This article is available from: http://www.molecularneurodegeneration.com/content/4/1/48 © 2009 Shankar and Walsh; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.