Table 2.

Overview of the functions of cysteine cathepsins in glial cells

Glial cell type	Cysteine cathepsin	Function	References
Microglia	Cathepsin B	Indirectly induces microglia-dependent Aβ accumulation in neurons via β-secretase activity	(Wu et al. 2017)
		Promotes Aβ phagocytic clearance in Alzheimer’s disease	(Cappellano et al. 2013; Comi and Tondo 2017; Nakanishi 2020b; Jiang et al. 2025)
		Activates the NLRP3 inflammasome and triggers IL-1β release via caspase-1	(Halle et al. 2008; Terada et al. 2010; Hanamsagar et al. 2011; An et al. 2016; Xu et al. 2018a; Bai et al. 2018; Chevriaux et al. 2020)
		Promotes neurotoxic polarization and neuroinflammation via NF-κB activation	(Wendt et al. 2009; Ni et al. 2015, 2019; Inoue et al. 2022)
		Impairs memory by degrading mitochondrial transcription factor A and producing reactive oxygen species and pro-inflammatory mediators	(Ni et al. 2019)
		Induces neuronal apoptosis via caspase-3 activation	(Kingham and Pocock 2001)
		Triggers apoptosis through Bid activation	(Zhang et al. 2023c)
	Cathepsin C	Promotes neurotoxic polarization and neuroinflammation via protein kinase C/p38MAPK/NF-κB activation	(Liu et al. 2019; Zhao et al. 2021)
		Enhances neuroinflammation by inducing C-C motif chemokine ligand 2 and C-X-C motif chemokine ligand 2	(Zhao et al. 2021)
	Cathepsin H	Promotes neurotoxic polarization, neuroinflammation, and neuronal death	(Fan et al. 2015)
	Cathepsin K	Promotes neurotoxic polarization and neuroinflammation	(Wendt et al. 2009)
	Cathepsin L	Disrupts microvessel integrity via extracellular matrix degradation	(Gu et al. 2015)
		Promotes neurotoxic polarization and neuroinflammation via NF-κB activation	(Xu et al. 2018b; Inoue et al. 2022; Zhang et al. 2025a)
		Activates the NLRP3 inflammasome	(Zhang et al. 2025a)
		Mediates major histocompatibility complex II antigen presentation	(Gresser et al. 2001)
	Cathepsin S	Promotes microglial activation and migration via extracellular matrix degradation	(Hai et al. 2007; Lively and Schlichter 2013; Lowry and Klegeris 2018)
		Promotes neurotoxic polarization and neuroinflammation via NF-κB activation	(Wendt et al. 2009; Zhang et al. 2025b)
		Processes the invariant chain to enable major histocompatibility complex II antigen presentation	(Nakagawa et al. 1999; Riese and Chapman 2000; Gresser et al. 2001)
	Cathepsin X	Abolishes γ-enolase neuroprotection against Aβ and lipopolysaccharide via proteolytic cleavage	(Obermajer et al. 2009; Hafner et al. 2013; Pišlar et al. 2017)
		Promotes neurotoxic polarization, apoptosis, and neuroinflammation via PI3K/Akt activation	(Wendt et al. 2009; Pišlar et al. 2017, 2020, 2022)
Astrocytes	Cathepsin B	Degrades Aβ and generates Aβ peptides	(Oberstein et al. 2020)
		Activates the NLRP3 inflammasome and triggers IL-1β release via caspase-1	(Qiao et al. 2016)
	Cathepsin C	Enhances neuroinflammation by inducing C-X-C motif chemokine ligand 2	(Zhao et al. 2021)
	Cathepsin K	Alters astrocyte number and phenotype	(Dauth et al. 2011)
	Cathepsin L	Mediates major histocompatibility complex II antigen presentation	(Gresser et al. 2001)
	Cathepsin S	Contributes to sensory impairment during neuroinflammation in EAE	(Kim et al. 2020)
Oligodendrocytes	Cathepsin X	Impairs oligodendrocyte maturation and differentiation	(Horvat et al. 2025)
*Cysteine cathepsins derived from microglia, astrocytes, and neurons affecting oligodendrocyte function.	Cathepsin B*	Impairs remyelination and promotes oligodendrocyte and neuronal damage	(Ma et al. 2007)
	Cathepsin C*	Enhances demyelination in EAE	(Durose et al. 2019)
		Enhances demyelination by inducing C-X-C motif chemokine ligand 2	(Liang et al. 2016)
		Produces toxic tumour necrosis factor-α and protective IL-1β and impairs myelin integrity Enhanhes T-cell expansion and tertiary lymphoid structures, resulting in earlier onset and more severe chronic EAE	(Shimizu et al. 2017) (Liu et al. 2025)
	Cathepsin H*	Contributes to EAE development	(Okada et al. 2018)
		Impairs remyelination and promotes oligodendrocyte and neuronal damage	(Ma et al. 2007)
	Cathepsin L*	Contributes to EAE development	(Allan and Yates 2015)
		Impairs remyelination and promotes oligodendrocyte and neuronal damage	(Ma et al. 2007)
	Cathepsin X*	Promotes IL-1β and neuroinflammation in EAE	(Allan et al. 2017)
	Cathepsin V*	Enhances demyelination	(Shimizu et al. 2017)

Aβ: amyloid beta, IL: interleukin, EAE: experimental autoimmune encephalomyelitis, NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells, NLRP3: NOD-leucine rich repeat and pyrin containing protein 3