Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder that progressively hinders cognitive and behavioral abilities. In individuals affected by the disease, cognitive decline is manifested by the impairment of memory, reasoning, judgement, visuospatial ability and language functions1. Behaviorally, unpredictable changes in personality become readily pronounced1. Corollary to the symptoms, the pathogenesis of AD is complex and multifaceted and involves ample changes in the brain. AD pathogenesis has been widely studied since 1906, when Alois Alzheimer diagnosed the first case after examining the brain tissue of Auguste D2. Alzheimers found copious amounts of lesions at the extracellular and intracellular level analogous to the now widely-known amyloid plaques and neurofibrillary tangles3,4. The formation of these two major histopathological hallmarks of AD were later determined to attribute to abnormal neuronal cell function, and eventually, to cell death3.
However, not until 1992 with the formulation of the “amyloid cascade” hypothesis, was it established that insoluble amyloid fibrils were formed by amyloid-beta (Aβ) peptides4. Research at the molecular level, determined that a precursor, single-pass transmembrane protein named amyloid precursor protein (APP) was responsible for the generation of these Aβ peptides4. In AD, the production of Aβ peptides (particularly those composed of 40-42 amino acids) from APP is greatly enhanced by mutations, some familial, in the APP gene or in the gamma-secretase protease, the enzyme that generates monomeric forms Aβ from APP4,7,15. Upon production, monomeric Aβ peptides, which themselves are nontoxic to nerve cells, self-association into toxic oligomeric forms takes place5.
Such findings gave rise to the “oligomer hypothesis” in 1998, which suggests that AD pathology is induced by these toxic oligomeric forms of Aβ formally known as amyloid-beta derived diffusible ligands (ADDLs)6. Furthermore, the hypothesis proposed that the initiating pathological event of AD was not neuronal cell death as was first predicted, but rather the loss of synaptic plasticity and long term potentiation (LTP) triggered by toxic ADDLs at the synaptosome level5,14.
Loss in synaptic plasticity, particularly loss in LTP leads to the impairment of short-term memory, which is often the most common reason bringing patients to the physician4. In most individuals, with the exception of those affected by early-onset AD, such symptoms first become apparent after the age of 6014. Being the leading cause of dementia in the elderly, it is estimated that 1 in 8 over the age of 65, and 1 in 2 over the age of 85 are affected by AD6. The progressively impairing nature of the disease, which is ultimately fatal, places a great social burden on the loved ones of those affected, and accounts for high medical and palliative costs4. Annually, it is estimated that AD costs the U.S. economy close to $200 billion, being the 3rd...