Neuronal Life Span Versus Health Span: Principles of Natural Selection at Work in the Degenerating Brain

Impaired nutrient delivery to the brain due to decreased blood flow contributes to cognitive decline and dementia in Alzheimer's disease (AD). Considering this, many studies have suggested that neuroprotective agents like those used in stroke could prevent AD onset or progression by promoting cell survival. However, research in the past decade suggests that the culprit behind the cognitive loss in AD models is actually the soluble tau accumulating inside of surviving neurons. In fact, tau reductions improve cognition in mouse models of AD, even those that only deposit amyloid plaques. There is emerging evidence that neuroprotection alone in these AD models may be insufficient to restore neuron function and cognition. Only when soluble tau is reduced on a neuroprotective background could memory be rescued. Thus, once a neuron begins to accumulate tau, it may survive in a malfunctioning capacity, leading to impaired electrical signaling and memory formation in the brain. These data imply that multiple drugs may be necessary to ameliorate the different disease components. In fact, strategies to preserve neurons without affecting the soluble protein burden within neurons may accelerate the disease course.