Yeast screening platform identifies FDA-approved drugs that reduce Aβ oligomerization.

Abstract

The older the average person alive today becomes, the more instances of neurodegeneration are observed worldwide. Alzheimer's disease is the most common neurodegenerative disorder preferentially affecting older individuals with 26.6 million cases recorded in 2006. It is estimated that worldwide prevalence will rise to 100 million cases by 2050 [1]. There is currently no effective treatment nor preventative therapy for Alzheimer's disease, and no definitive diagnosis besides post-mortem pathology. Diagnosis is based on the presence of intracellular inclusions of hyperphosphorylated microtubule associated protein tau and extracellular plaques consisting of amyloid beta (Aβ) peptide [2]. Aβ is a small peptide 40-42 aa in length, formed via amyloid precursor protein (APP) cleavage that results in Aβ release into the extracellular space. Aβ is normally observed circulating in the cerebrospinal fluid of mammals, and is produced mostly in the central nervous system [3]. Although Aβ aggregates are the major pathological hallmark of Alzheimer’s disease, the mechanisms of Aβ induced neurotoxicity is not well understood, and even less is known about the physiological function of Aβ peptide. Absence of APP results in embryonic development defects due to irregular migration of cerebral cortex neurons [4]. Recent work also indicates that Aβ peptide concentrations in the CNS modulate synaptic transmission and synaptic hyperactivity via direct binding to APP [5]. In addition to the pathological connection between Aβ deposition and Alzheimer’s, a genetic connection has been mapped as well. Multiple mutations in APP and its cleaving enzymes increase the risk of Alzheimer disease onset [6-8]. Some mutations alter the cleavage of APP, resulting in a shifted ratio of Aβ1-42 to Aβ1-40, thus increasing the proportion of the more aggregation-prone species. Other mutations affect the aggregation propensity of the Aβ1-40/42 peptide itself [9]. As with another aggregation-prone disease associated protein, α-synuclein in Parkinson’s disease, an increase in Aβ production results in its aggregation and the early onset of Alzheimer’s disease [10]. While most models of Aβ cellular pathology assume that toxicity stems from its aggregation propensity [11], there has been vigorous debate about whether the toxicity stems mostly from extracellular high-molecular weight amyloid plaques, or mostly from the low molecular weight oligomers [12-14]. Aβ can be re-incorporated into the cytoplasm after extra-cellular cleavage, and much evidence has accumulated over the past several years that favors the small intracellular oligomers as the toxic aggregate species [15]. Particularly convincing are seminal studies in simple models of disease: C. elegans and mice, demonstrating a link between aging, insulin signaling, and toxicity driven by low molecular weight oligomers of Aβ [16-18]. Another study, modeling Alzheimer's disease in mice, showed that cognitive impairment precedes mature fibrillar deposits [19]. Due to the multifaceted and multifactorial nature of Alzheimer’s physiology, no single model can fully recapitulate disease. Mice are currently the model system that most closely resembles human beings while still being capable of exhibiting features of aging on a time-scale in line with the duration of a typical PhD or postdoc. Mice can also be scored for learning and memory defects, as well as motor neuron function. However, it is equally the case that a mouse that is artificially expressing extremely high amounts of Aβ in its brain will not accurately recapitulate the memory neuronal circuits of a 75-year-old human being. At the same time, mammalian models are sometimes less tractable and may offer less molecular and cellular detail of pathology and toxic events. Simpler models of Aβ toxicity have been exploited with tremendous success towards greatly improving our understanding of the cellular pathology of molecular events associated with Alzheimer’s, as well as other neurodegenera-