Table 2 Summary of 6 KI/KO mouse models of AD
Name | Mutation | Phenotype/Pathology | Behavior | Additional | Ref |
|---|---|---|---|---|---|
APP KI | APP NL | N/A | Increase of anxiogenic-like behavior (15 mo). | Lack of tau pathology and no decline in spatial learning and memory. | |
APP GF | Initial Aβ deposition (4 mo); Aβ deposition in a much larger brain area than in APP NLF or APP NLGF mice (12 mo). | N/A | N/A | ||
APP NLGF | Cortical Aβ amyloidosis (2 mo) and saturated by 7 mo. Consistent subcortical amyloidosis (4 mo). Greater microgliosis and astrocytosis than NL-F mice (9 mo). | Decline in spatial learning but retained memory (8 mo). Anxiolytic-like behavior (15 mo). Hyper-reactivity to pain stimuli (15–18 mo). | N/A | ||
APP SAA | Amyloid deposition detectable (4 mo). Increase of total brain density of Aβ plaques with highest burden in the cortex and hippocampus (8 mo). | Robust hyperactivity (18 mo). | Female: more pronounced hyperactivity (8 mo). | ||
APP NL-F | High production of Aβ42 with the highest ratio of Aβ42/Aβ40. Initial deposition of Aβ (6 mo). Cortical amyloidosis (24 mo). Accumulation of microglia and activated astrocytes, and neuroinflammation near Aβ plaques. | Memory impairment (18 mo). | Provide a better frame for upstream factors that affect Aβ amyloidosis than other mutations. | ||
Tau KI | Exons 1 to 14 of mMAPT replaced with hMAPT | Normal axonal localization of tau. | N/A | Little difference compared to WT in phenotype. Often crossed with other models. MAPT P290S KI developed murine tau aggregates. | |
MAPT KI x APP NLGF | Faster spread of pathological tau (19 mo). Tau humanization did not affect A beta or neuroinflammation. | Tau humanization did not affect memory | More tau accumulation in the presence of amyloidosis. APP NLGF x MAPT P290S dKI mice demonstrated more tau inclusions than age matched MAPT P290S KI mice. dKI mice also demonstrated tau seeding abilities. | ||
5xFAD x MAPT KI | Tau humanization suggested to have a protective effect against AD. Seemed to offset LTP impairment compared to WT. | Decrease of anxiogenic-like behavior and better spatial learning compared to 5xFAD | Enrichment in lysosome, phagocytosis,and ocidative phosphorylation by GSEA compared to 5xFAD and human co-expression modules. | ||
APOE KI | Target replacement ApoE KI | E4FAD accumulation of Aβ42, tau hyperphosphorylation (1–4 mo), neuronal loss, deterioration of BBB, and reduced cerebral blood flow compared to E3FAD mice. | Female APOE4 KI mice have significant deficits in learning and memory. E4FAD mice developed hippocampal-associated memory deficits and had a substantial drop in nest construction scores compared to E3FAD mice. | Female: E3FAD and E4FAD have significantly higher Aβ42 and Aβ40 levels than male counterparts. Female E4FAD more deficits in learning and memory. Other deficits such as phospholipid and cholesterol dysregulation, microglial dysfunction, neuroinflammation, and taupathy-related neurodegeneration. | [105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128] |
Floxed APOE KI | APOE protein found in astrocytes but not in reactive Iba-1 positive microglia. | N/A | Typically used to cross with other transgenic models like APP/PS1 mice or PS19 mice. Overall cerebral accumulation of amyloid plaques in APOE4 KI mice crossed with APP/PS1 mice was not affected. PS19-E4 crossed mice demonstrated higher degree of neurodegeneration. | ||
APOE KI: JAX | Female APOE4 KI JAX mice had lower plasma Aβ42 and a decreased Aβ42/40 ratio. However, there were no differences between APOE4 and APOE3 KI mice. Aβ40 levels did not differ regardless of APOE genotype or sex. | Locomotor activity, motor coordination, and working memory tested by open field, rotarod, and Y-maze tests, respectively were similar between APOE4 KI and control mice with an age-depedent decline (2 mo and 12 mo). | It is suggested that there are higher levels of aggregate-prone Aβ42 in the brain in female APOE4 KI mice compared to their male counterparts. | ||
TREM2 KO | Del exons 3 and 4 | Reduced microglial numbers and size, decreased myelin repair. Prolonged microgliosis, impaired cholesterol transport. | Decreased performance on motor coordination tests (12 mo) when fed with CPZ | No apparent neurological phenotypes except for impaired immune response and altered transcriptome. TREM2 deficiency increased early-stage plaque growth, but not overall plaque deposition in an APP/PS1 dE9 mouse model with human APOE3 or APOE4. | |
TREM2 KO x 5xFAD; TREM2 R47H x 5xFAD | High levels of amyloid in hippocampus and reduced IBA1 expression near plaques (8 mo). | N/A | Microglia are less viable than TREM2 + / + 5xFAD mice with reduced levels of CSF-1. Decreased TREM2 shedding with imparied downstream signaling in TREM2 R47H x5xFAD mice. | ||
TREM2 KO x PS19 | Less neurodegeneration and microgliosis compared to PS19 mice. No differences in p-tau levels and tau solubility. | N/A | Decreased inflammatory markers. Suggests that severe microglia response can contribute to neurodegeneration. | ||
hTREM2 KI | TREM2 CV and TREM2 R47H by Song et al. | Impaired lipid sensing and DAM responses to amyloid. Impaired soluble TREM2 cell-surface interactions with decreased TREM2 shedding noted on neurons. | N/A | Mice developed less brain atrophy and synaptic loss with diminished microglial reactivity and phagocytosis when compared to PS19-TREM2(CV) mice. | |
TREM2 R47H and APPPS21-TREM2 + /R47H by Cheng-Hathaway et al. | Attenuated microglial response to amyloid with reduced amounts of dense-core plaques. TREM2 R47H mice with cuprizone-induced neuro-inflammation demonstrated age-depedent impairments in microglial interaction with plaques (4 mo), and LTP and synaptic loss (12 mo). | N/A | Attenuated microglial response to amyloid with increased neurite dystrophy. | ||
LOAD1, LOAD2 and others by JAX | No amyloid plaques or other AD hallmark changes observed in LOAD1 mouse models even at 24 months of age. After high fat diet (HFD) treatment, LOAD2 mice demonstrated neuronal loss and elevated brain Aβ42 (16 mo). | No cognitive deficits observed in LOAD1 mouse models even at 24 months of age. LOAD2 mice on HFD exhibited behavioral deficits. | Reduction in brain TREM2 protein levels and changes in circulating cytokine levels. Regional changes in glycolysis and vascular perfusion. Female LOAD1 mice showed increased risks of mortality and glycolysis was significantly altered (4 mo-12 mo). | ||
hTREM2 Tg | BAC TREM2 Tg | Reduced mamyloid plaques with associated gene signature changes including dampened damage-associated microglial gene expression and up-regulated neuronal gene expression. | Cognitive performance improved in BAC hTREM2 Tg x 5xFAD mice compared to 5xFAD mice with increased phagocytic microglia and reduced neurite dystrophy seen. | N/A |