TABLE 4

Cathepsin B Gene Knockout Improves Memory Deficits in AD and Aging Models

Animal Model	hAPP Isotype			CTSB Knockout Improves Memory Deficits and Outcomes in hAPP AD Models			References
	Isotype, Cell Type	β-Secretase Site	γ-Secretase Site	Memory Deficits	Cellular and Biomarker Features	Pathology
Aging	Mouse APP isoforms of 695 in neurons and isoforms 751 and 770 in glia	WT	WT	↓Memory deficits	↓Activated macrophages, ↓inflammatory cytokines, ↓oxidative stress, ↑long-term potentiation	nd	Terada et al., 2010; Ni et al., 2019
Periodontitis AD	Mouse APP isoforms of 695 in neurons and 751 and 770 in glia	WT	WT	↓Memory deficits	↓Activated macrophages ↓Aβ (1-42), ↓inflammatory cytokines	nd	Wu et al., 2017
AD	hAPP-WT-695, neuronal expression (PDGF promoter)	WT	WT	n/a	↓Aβ (1–42) by ∼70% ↓β (1–40) by ∼70% ↓CTFβ by 40%, ↑sAPPα by 60%, ↓WT β-secretase activity	n/a	Hook et al., 2009
AD	hAPP-WT-Lon-695, neuronal expression (PDGF promoter)	WT	Lon, V717I	↓Memory deficits	↓Aβ(1–40) by 85% ↓Aβ(1–42) by 87% ↓pGluAβ(3–40) by 65% ↓pGluAβ(3–42) by 92% ↓CTFβ by 60% ↑sAβPPα by 60% ↓WT β-secretase activity	↓Aβ plaque by 85%, ↓pGluAβ plaque by 46%	Kindy et al., 2012; Hook et al., 2014b
AD	hAPP-Swe-Lon-695, neuronal expression (PDGF promoter)	Swe, K670N/M671L	Lon, V717I	No effect on memory deficits	No effects on Aβ(1–42), CTFβ, or APPα	No effect on amyloid plaque	Kindy et al., 2012
AD	hAPP-Swe-Ind-695, neuronal expression (PDGF promoter)	Swe K670N/M671L	Ind, V717F	n/a	No effects on Aβ, CTFβ, or sAPPα	n/a	Hook et al., 2009
AD	hAPP-Swe-Ind-751/770, neuronal expression (PDGF promoter), J20 line, introns modified, PDAPP)	Swe	Ind	nd	No change in fIAPP, β-CTF, α-sAPP, or α-CTF ↑Aβ(1–42)/Aβ(1–x) ratio by ∼25%	Elevated plaque load	Mueller-Steiner et al., 2006
AD	hAPP-751/770, neuronal expression (PDGF promoter, I63 line, introns modified, PDAPP)	WT	WT	nd	No change in hippocampal Aβ42, ↑cortical Aβ42 by 12%	nd	Wang et al., 2012

nd, not determined; n/a, not applicable.