Abstract:

Alzheimer’s disease (AD), the predominant form of dementia, is a chronic,incurable neurodegenerative disorder presenting with symptoms including progressive memory loss and disturbed emotional state. It has been estimated that dementia affects over 47 million people worldwide, and with 60–80% of cases attributable to AD. The primary pathological hallmarks of AD are neuronal death, the deposition of insoluble amyloid-beta (Aβ) plaques, the accumulation of hyperphosphorylated tau neurofibrillary tangles (NFTs), and the widespread dysregulation of neurotransmitter signaling. Although the aetiology of the disease is not clearly understood, a range of theories have been proposed over the last few decades. The amyloid hypothesis holds that the anomalous processing of the amyloid precursor protein (APP) to Aβ and its deposition as insoluble plaques is the primary mechanism underlying AD pathogenesis, while the tau hypothesis contends that the hyperphosphorylation of tau and NFT formation is central to the disease process. Others have proposed the contribution of neuroinflammatory pathways, vascular dysfunction, oxidative stress,mitochondrial dysfunction, changes in metal ion regulation, and abnormal insulin signaling. It is widely accepted that the excitatory glutamatergic and cholinergic systems are severely affected in AD, due to the significant loss of cells in these systems and the disruption of their molecular components. As a result, the excitatory/inhibitory (E/I) balance is disturbed in the AD brain, and this could well underlie the deficiencies in memory and learning that are characteristic of the condition. At present, all five drugs approved by the US Food and Drug Administration for the symptomatic treatment of AD are targeted towards these systems –including the acetylcholinesterase inhibitors donepezil, rivastigmine and galantamine, and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine. However, these therapies do not address the underlying causes of the disease and there is an urgent need for the identification of novel therapeutic targets.