Millions of people suffer from the devastating consequences of age-related dementias such as Alzheimer's disease (AD). This number will only increase as our lifespan extends. The histological signatures of AD in patient's brains are neurofibrillary tangles and plaques, consisting of amyloidogenic proteins, including Tau and amyloid-beta (A?). Recent evidence now suggests that the observed cytotoxic effects of AD are less caused by the mature A? fibrils than by toxic oligomers, which are transiently produced on the pathway of amyloid formation, or generated by the shedding of mature fibrils. These results suggest that amyloidogenic modifiers that accelerate fibril formation and/or stabilize mature fibrils will reduce the cytotoxic effects of A?. We have recently discovered that polyphosphate (polyP), one of the structurally simplest, conserved and ubiquitous biopolymers found in biology, serves as a protein-binding scaffold that stabilizes amyloidogenic proteins in a ?- sheet conformation. This accelerates fibril formation and stabilizes mature fibrils. Importantly, we found that polyP decreases amyloid toxicity in differentiated neurons, and delays paralysis in C. elegans models of A? toxicity. These results are consistent with a model in which polyP-mediated acceleration of the fibril-forming process reduces A? toxicity by reducing accumulation of potentially toxic intermediates, and raise the exciting possibility that we have discovered a physiologically relevant modifier of A? fibril formation. Given that polyP levels in vertebrate brains have been found to dramatically decrease with age, we propose that this age- mediated polyP decline contributes to the observed predisposition of older patients towards AD and other amyloidogenic diseases. We will now characterize how polyP affects in vivo A? amyloid formation and toxicity using a C. elegans AD model (Aim 1). Moreover, we will test how brain polyP levels correlate with human AD progression and attempt to manipulate brain polyP levels in a mouse model of AD, assess any related behavioral changes and determine how changes in endogenous polyP levels affect soluble and fibrillar A? levels in AD mouse brains (Aim 2). Together, these experiments will provide us with crucial information about how polyP levels correlate with histopathological AD markers and/or with AD severity during disease progression. They will also reveal whether changing polyP levels affects the abundance of specific A? species in AD model brain. This work will form the necessary groundwork for future in vivo experiments, aimed at directly determining whether levels of endogenous polyP influence onset and/or disease outcome in AD model mice.
Millions of people suffer from the devastating consequences of age-related dementias such as Alzheimer's Disease (AD). We have recently discovered that polyphosphate, an abundant and ubiquitous cellular polymer, protects cells and organisms against the toxic effects of amyloidogenic proteins including amyloid-beta (A?), a causative agent in AD. We will now determine how changes in endogenous polyphosphate levels affect A? amyloidogenic processes and may potentially alter mechanisms of AD pathogenesis.
| Ungvari, Zoltan; Tarantini, Stefano; Donato, Anthony J et al. (2018) Mechanisms of Vascular Aging. Circ Res 123:849-867 |
