Table 2.

ApoE mice studies.

Author (year)	Animal model	Age (months)	Measure	Findings	Conclusion
Nathan et al. [101]	ApoE KO mice; WT C57BL/6 strain	4 months	BFP test; OC test; OCTA test.	ApoE KO mice performed poorly in all three tests compared to WT mice, while they learned the tasks at a rate comparable to WT mice. Latency to find the buried pellet was significantly longer in ApoE KO mice than WT mice. ApoE KO mice did not differentiate the odorant and failed the avoidance test.	ApoE deficiency in ApoE KO mice leads to a deficit in olfactory function, suggesting an important role for ApoE in the olfactory system.
Nathan et al. [103]	ApoE KO mice; WT C57BL/6 strain	2–3 months	OE Lesion; IHC of OB tissue (0, 3, 7, 21, 42, and 56 days post-lesion)	Slow OMP recovery in the OB in ApoE KO compared to WT mice. Recovery of glomerular area was similarly slower. GAP43 accumulation and restore in the OB were slower in KO mice.	Olfactory nerve regeneration is significantly slower in KO mice, suggesting ApoE participates in olfactory nerve regeneration.
MC Asey et al. [113]	ApoE KO mice; WT C57BL/6 strain	2–4 months	Ovariectomy. Estradiol replacement. IHC of Olfactory tissues (5, 14, 28 and 49 days after OVX and pellet replacement).	GFAP concentrations were higher in the E2-deprived mice but did not increase in the E2-replaced group at 49 days. Syn and ApoE concentrations were significantly ↑ by 15% and 25%, respectively, in the E2-replaced compared to the vehicle-replaced group at 5 days, but by 14 days concentrations were equivalent.	Estradiol is able to suppress reactive gliosis. In addition, E2 replacement in OVX mice is associated with transiently higher levels of ApoE and Syn.
Nathan et al. [102]	ApoE KO mice; WT C57BL/6 strain	4 months	IHC staining of OB and OE tissues fpr ApoE iimunoreactivity	The perikarya and processes of sustentacular (Sus) cells expressed ApoE-like immunoreactivity. The endothelial cells of blood vessels were intensely stained for ApoE in the lamina propria. Cells forming Bowman’s gland also immunostained for ApoE. The ApoE staining in the nerve fascicles was less intense, but was uniformly distributed throughout the core of the nerve bundles. Ensheathing glia, surrounding the nerve fascicles also stained heavily for ApoE.	ApoE is expressed in the adult OE and lamina propria at strategic locations where it could facilitate the differentiation, maturation and axonal growth of the ORN, perhaps by recycling lipids from degenerating ORN for use by growing axons.
Cheng et al. [112]	ApoE KO mice; WT C57BL/6 strain	2–4 months	Ovariectomy; Estradiol (E2) replacement; IHC staining of olfactory tissues.	Five days of E2 replacement significantly ↑ LRP expression in the hippocampus, OB and neocortex but not in cerebellum. In contrast, E2 treatment ↓ LRP expression in OB.	Hormone therapy (HT) modification of both ApoE and LRP could have wide-spread effects on cellular function given LRP’s manifold signaling functions.
Nwosu et al. [105]	ApoE KO mice; WT C57BL/6 strain	2–4 months	OE Lesion; IHC and IB staining of OB tissue (0, 3, 7, 21, 42, and 56 days post-nasal irrigation).	Sharp ↓ in concentrations of Syn in OB following injury in both WT and KO mice during the degenerative phase (3–7 days). Syn concentration in KO mice did not recover by day 56 whereas Syn density in WT was essentially restored to normal. IHC of glomerular Syn density revealed a lower density in KO mice at all-time points post lesion. Lower concentration of whole bulb Syn parallels the slower recovery of glomerular area in KO mice.	In the absence of ApoE, synaptic recovery in whole bulb samples is substantially delayed compared to WT mice.
Nathan et al. [106]	ApoE KO mice; WT C57BL/6 strain	2–4 months	OE Lesion; Tissue preparation (0, 3, 7, 21, 42, and 56 days post-treatment); IB; IHC	ApoE expression in the OE is highly regulated during the entire course of OE reconstitution post injury, and ApoE deficiency in ApoE KO mice leads to delayed recovery of mature OMP+ cells in the reconstituting OE.	ApoE production increases in the injured OE to facilitate maturation of olfactory sensory neurons.
Nathan et al. [106]	ApoE KO mice; WT C57BL/6 strain	4 months	Ovariectomy; BrdU injections, Olfactory turbinates tissues; IHC	3 days of estradiol replacement ↑ ApoE expression in the olfactory nerve and in the glomerular layer. Estradiol treatment also ↑cell proliferation, total cell numbers, number of mature neurons in the olfactory epithelium, and reactive astrocyte numbers in the OB in both WT and KO mice. Estradiol ↑ glomerular synaptophysin (Syn), but the magnitude of increase was potentiated by the presence of ApoE.	ApoE may be required to elicit the complete effect of estradiol on Syn upregulation.
Nathan et al. [110]	ApoE KO mice; WT C57BL/6 strain	2–4 months	Ovariectomy; BrdU injections, Olfactory tissues; IHC	Estradiol replacement ↑ ApoE staining in the olfactory nerve and glomerular layers. Estradiol ↑ astrocyte density and OE thickness regardless of the genotype. Estradiol treatment ↑ the number of mature neurons in the OE and glomerular synaptophysin in both genotypes, but the magnitude of increase was greater in the WT than in the KO mice.	Estrogen and ApoE act synergistically to minimize the loss of mature sensory neurons and synapses following ovariectomy.
Hussain et al. [104]	ApoE KO mice; WT C57BL/6 J mice	post-natal pups (2 days old)	Olfactory explant epithelial culture; Immunocytochemistry; Measurement of neuronal numbers, halo size, and neurite outgrowth	The OE cultures derived from ApoE KO mice have significantly ↓ neurons with shorter neurite outgrowth than cultures from WT mice. Treatment with either purified human ApoE2 or with human ApoE3, but not ApoE4, significantly ↑ neurite outgrowth. The differential effects of human ApoE isoforms on neurite outgrowth were abolished by blocking the LRP with lactoferrin and RAP.	ApoE2 and ApoE3 stimulate neurite outgrowth in OE cultures by interacting with the LRP. ApoE4, the isoform associated with AD, failed to promote neurite outgrowth, suggesting a potential mechanism whereby apoE4 may lead to olfactory dysfunction in AD patients.
Peng et al. [100]	knock-in mice humanized to ApoE4 versus ApoE3	6 months; 12 months	Olfactory Perceptual Memory; in vivo resting and odor-evoked local field potentials (LPF)	Young ApoE4 compared to ApoE3 mice exhibited a behavioral olfactory deficit coinciding with hyperactive odor-evoked response magnitudes within the OB that were not observed in older ApoE4 mice; shift with aging in ApoE4−driven effects from OB to PCX;	Early ApoE4−driven olfactory memory impairments and OB network abnormalities may be a precursor to later network dysfunction in the PCX, a region that not only is targeted early in AD, but may be selectively vulnerable to ApoE4 genotype.

Note: AD Alzheimer’s disease, BFP buried food pellet, BrdU bromodeoxyuridine, GAP 43 growth associated protein 43, GFAP Glial fibrillary acidic protein, IB immunoblotting, IHC immunohistochemistry, LRP low-density lipoprotein (LDL) receptor related protein, OB olfactory bulb, OC odor choice, OCTA odor cued taste avoidance, OE olfactory epithelium, OMP olfactory marker protein, ORN olfactory receptor neuron, OVX ovariectomized, PCX piriform cortex, RAP receptor-associated protein, Syn synaptophysin (a synaptic marker).