Neuronal life span versus health span: principles of natural selection at work in the degenerating brain - PubMed (original) (raw)

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Neuronal life span versus health span: principles of natural selection at work in the degenerating brain

John C O'Leary 3rd et al. J Mol Neurosci. 2011 Nov.

Abstract

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.

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Figures

Figure 1

Sub-optimally functioning neurons surviving with proteotoxic tau accumulation subvert brain plasticity that normally occurs in response to neuronal death. (A) Neuronal transmission in normal brain. (B) Sub-optimally performing neurons due to tau accumulation cannot transmit a signal to the post-synaptic neuron, and the brain fails to re-route connectivity since the neuron is not dead. (C) Neuronal death facilitates network re-routing, allowing the plastic brain to adapt and re-establish downstream connectivity.

Cited by

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau.
Blair LJ, Nordhues BA, Hill SE, Scaglione KM, O'Leary JC 3rd, Fontaine SN, Breydo L, Zhang B, Li P, Wang L, Cotman C, Paulson HL, Muschol M, Uversky VN, Klengel T, Binder EB, Kayed R, Golde TE, Berchtold N, Dickey CA. Blair LJ, et al. J Clin Invest. 2013 Oct;123(10):4158-69. doi: 10.1172/JCI69003. Epub 2013 Sep 3. J Clin Invest. 2013. PMID: 23999428 Free PMC article.

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Neuronal life span versus health span: principles of natural selection at work in the degenerating brain - PubMed (original) (raw)