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Selective vulnerability in neurodegenerative diseases

Abstract

Neurodegenerative diseases have two general characteristics that are so fundamental we usually take them for granted. The first is that the pathology associated with the disease only affects particular neurons (‘selective neuronal vulnerability’); the second is that the pathology worsens with time and impacts more regions in a stereotypical and predictable fashion. The mechanisms underpinning selective neuronal and regional vulnerability have been difficult to dissect, but the recent application of whole-genome technologies, the development of mouse models that reproduce spatial and temporal features of the pathology, and the identification of intrinsic morphological, electrophysiological, and biochemical properties of vulnerable neurons are beginning to shed some light on these fundamental features of neurodegenerative diseases. Here we detail our emerging understanding of the underlying biology of selective neuronal vulnerability and outline some of the areas in which our understanding is incomplete.

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Fig. 1: Regions and neurons that are vulnerable in neurodegenerative diseases.

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Acknowledgements

The authors thank D. Dickson for critical reading of the manuscript. K.E.D. acknowledges the support of NIH (NS074874 and AG056151), Cure Alzheimer’s Fund, the Tau Consortium, and the Brightfocus Foundation. This work was also supported by a grant from the NIH (AG056673) and the Alzheimer’s Association (AARF-17-505009) to H.J.F.

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Fu, H., Hardy, J. & Duff, K.E. Selective vulnerability in neurodegenerative diseases. Nat Neurosci 21, 1350–1358 (2018). https://doi.org/10.1038/s41593-018-0221-2

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