Table 2.

Summary: Cellular level determinants of region-specific vulnerability.

Archetypal neurodegenerative disease-associated region	Cellular level mechanisms of regional ageing/susceptibility to neurodegenerative disease	Key references
Hippocampus	Decline in hippocampal neurogenesis (rodents/primates)	Ben Abdallah et al., 2010 Leuner et al., 2007
	Fewer Doublecortin expressing cells in the human dentate gyrus	Knoth et al., 2010
	Reduction in quiescent neural progenitors and angiogenesis in dentate gyrus	Boldrini et al., 2018
	Regional loss of hippocampal NeuN expressing neurons and nonneuronal cells	Fu et al., 2015
	Large/long hippocampal neurons are selectively vulnerable to ageing	Mattson and Magnus, 2006
	Hippocampal CA1 neurons are selectively vulnerable to oxidative stress	Wang and Michaelis, 2010
	Relatively larger changes in astrocyte-specific gene expression with ageing	Soreq et al., 2017
	Region with relatively more astrocyte expression changes with ageing	Clarke et al., 2018
	Elevated astrocytic proinflammatory phenotype compared to other regions on ageing	Clarke et al., 2018
	Lower capacity of hippocampal astrocytes to respond to injury	Cragnolini et al., 2018
	Loss of unique microglial regional identity on ageing; reduced engagement with niche	Grabert et al., 2016
	Regionally susceptible to breakdown of blood-brain barrier	Montagne et al., 2015
Substantia Nigra	Loss of pigmented and tyrosine hydroxylase expressing neurons	Rudow et al., 2008
	Higher levels of neuronal loss than other regions	Reeve et al., 2014
	Long substantia nigra dopaminergic neurons are selectively vulnerable to ageing	Mattson and Magnus, 2006
	SN pars compacta neurons are selectively vulnerable to oxidative stress	Wang and Michaelis, 2010
	Relatively larger changes in astrocyte-specific gene expression with ageing	Soreq et al., 2017
	SN astrocytes were less protective than their VTA counterparts	Kostuk et al., 2019
	High abundance of microglia and regional vulnerability to neuroinflammatory insult	Kim et al., 2000
Spinal Cord	Most structurally dynamic with ageing in terms of neuronal number/density	Fu et al., 2015
	Loss of lumbosacral motor neurons	Tomlinson and Irving, 1977
	Large/long lower motor neurons are selectively vulnerable to ageing	Mattson and Magnus, 2006
	Motor neurons are exposed to higher oxidative stress and may be more susceptible to ageing	Shaw and Eggett, 2000
	Increase in nonneuronal cell abundance with ageing	Fu et al., 2015
	Spinal cord microglia more susceptible to ageing than their brain counterparts	Ritzel et al., 2015
	Age-related increase in blood-spinal cord barrier permeability, highest in the ventral horn	Piekarz et al., 2020