Table 2.
Effects of vitamin D in experimental models of Alzheimer’s disease—in vivo studies.
| AD Model | Vitamin D Administration | Effects | References |
|---|---|---|---|
| The human amyloid precursor protein-expressing models-Tg2576 and TgCRND8 mice | calcitriol (2.5 μg/kg, i.p., q2d × 4) | ↑ brain P-glycoprotein ↓ soluble and insoluble plaque-associated Aβ ↑ conditioned fear memory |
[96] |
| Intrahippocampal injection of Aβ(1−42) in rats Intraventricular injection of Aβ(1−42) in mice |
calcitriol (1 μg/kg)/day/6 consecutive days before the hippocampal delivery of aggregated Aβ(1−42) and at days 8,11,13,15,18 after Aβ(1−42) calcitriol (1 μg/kg)/day/5 days before Aβ(1−42) and at days 8 and 12 after Aβ(1−42) |
↓ neuronal damage in CA1 ↑ neurogenesis in dentate gyrus |
[97] |
| Rats at different ages (5, 12 and 24 months) | cholecalciferol (500 IU/kg, orally)/day/5 weeks | ↑ brain BDNF level, AChE, antioxidant enzymes; ↓ malondialdehyde level, caspase-3 activity |
[94] |
| APPswe/PS1E9 and C57BL/6J mice | calcitriol (100 ng/kg), i.p./daily/6 weeks | ↑ learning and memory abilities ↓ morphological defects in hippocampal neurons ↓ caspase-3, Bax ↑ Bcl-2, VDR, p-ERK1 |
[100] |
| AβPP-PS1-transgenic mice | cholecalciferol (control diet, 2.4 IU/g), (Surplus vitamin D diet ~12 IU/g) or (vitamin D deficient diet, 0 IU/g) | ↓ the number of amyloid plaques, Aβ peptides, TNF-α ↑ NGF |
[101] |
| Two-month-old wild-type (B6C3) and AD transgenic (APPSwe/PS1dE9) mice | Diet deficient in vitamin D2 or a diet supplemented with vitamin-D2-enriched mushrooms (VDM), containing 160.2 mg/kg (54 IU/kg) vitamin D2/7 months | ↑ learning and memory ↓ amyloid plaque load and glial fibrillary acidic protein ↑ interleukin-10 in the brain of VDM-fed wild type and AD transgenic mice |
[102] |
| Intracerebroventricular STZ injection in rats | STZ (1.5 mg/kg)/first and third day cholecalciferol (42 IU, oral gavage)/day/pre-treatment 7 days before STZ/21 days and post-treatment 24 h after STZ/21 days |
↑ spatial learning and memory functions ↓ neuronal oxidative stress ↓ mitochondrial aberrations ↑ cholinergic functions ↓ hippocampal neuroinflammatory response ↓ neuronal death in cortex and hippocampus |
[104] |
| LPS-induced hippocampal damage in rats | Maxacalcitol (1 μg/kg, i.p.)/twice a day/4 weeks LPS (0.8 mg/kg, i.p./once a week/3 weeks before maxacalcitol |
↓ TNF-α, MDA, ↑ Nrf2 ↑ IL-10, HO-1, GSH ↓ Aβ, p-Tau ↓ MAPK-p38, ERK1/2 ↓ neuronal damage in CA1 ↑ cognitive functions |
[105] |
| APP/PS1-transgenic mice | Paricalcitol (200 ng/kg)/once every two days/15 weeks | ↓ the iron accumulation in the cortex and hippocampus ↓ Transferrin receptor (TFR) and iron-regulatory protein 2 (IRP2) expression ↓ phosphorylation of Tau at Ser396 and Thr181 sites via inhibiting the GSK3β phosphorylation (Tyr216) |
[106] |
| APPswe/PS1E9-transgenic mice | eriodictyol (50 mg/kg, i.p.)/3 times per week | ↑ Nrf2/HO-1 ↑ VDR expression ↓ ferroptosis |
[107] |
| D-galactose-induced oxidative stress in mice | cholecalciferol (100 μg/kg i.p.)/3 times a week/4 weeks | ↑ the neuronal synapse and memory ↓ oxidative stress ↑ NRF-2, HO-1 ↓ NF-κB, TNF-α, IL-1β |
[103] |
| mouse brain homogenates from WT and vitamin D deficient C57BL/6 mice | calcifediol, maxacalcitol, calcipotriol, alfacalcidol, paricalcitol, doxercalciferol (100 nM)/24 h |
↑ Aβ-degradation ↓ β-secretase 1 |
[113] |
| 5XFAD transgenic mice (Transcriptomic analysis) | cholecalciferol (7500 IU/kg)/5 months | improved dysregulated pathways related to immune, inflammatory response, neurotransmitter activity, endothelial, vascular processes, hormonal alterations | [114] |
| Kun Ming mice | calciriol (2.5 μg/kg, i.p./day/14 days | ↑ LRP-1 expression ↑ VDR expression |
[59] |
| Aging model in C57BL/6 fed a normal or high-fat/high-cholesterol diet | calcitriol (2.5 μg/kg, i.p.)/day/week | ↑ P-glycoprotein expression |
[93] |
| APP/PS1-transgenic mice | Paricalcitol (200 ng/kg, i.p.)/once every two days/15 weeks | ↓ Aβ generation and neuronal loss ↑ LRP-1 expression ↑ lysosomal degradation of BACE1 ↓ 8-hydroxyguanosine generation in neuronal mitochondria resulting in the attenuation of calpain-1-mediated neuronal loss |
[117] |
| LPS-treated rats | LPS (0.8 mg/kg, i.p.)/once a week/3 weeks + vitamin D3 (1 μg/kg)/twice a day/4 weeks and/or exercise (30 min/once daily/4 weeks | ↑ cognitive dysfunction ↓ IL-6, MDA, Aβ, tau proteins levels ↑ IL-10, GSH, AChE, dopamine, BDNF, NGF |
[102] |
| UCMS rat model | Vitamin D3 (100, 1000, 10,000 IU/kg, i.p.)/4 weeks during UCMS | ↓ corticosterone ↑ spatial learning and memory ↓ oxidative stress ↓ Aβ ↑ BDNF |
[118] |
| eNOS-deficient mice | - | ↑ APP, BACE1, Aβ peptides | [120] |
| APP/PS-1 double-transgenic (2xTg-AD) mice | - | ↓ PGC-1α ↓ VDR |
[123] |
| Intrahippocampal Aβ(1–40) peptide injection in rats | calcitriol (1 µg/mL×1 mL/kg, i.p.)/day/14 days | ↑ learning and memory ↓ neuronal loss and oxidative stress (↓ MDA, ↑ SOD) |
[111] |
| Intrahippocampal injection of Aβ(1–40) peptide in rats | cholecalciferol (5 μg/kg/day, i.p.)/2 weeks | ↓ Aβ-induced memory impairment ↑ antioxidant markers (TAC, TTG) ↓ stress oxidative biomarkers (LPO, DNA damage) |
[112] |
| Double-transgenic APP/PS1 mice | vitamin D3-sufficient diet (600 IU/Kg of cholecalciferol) vitamin D3-supplemented diet (8044 IU/Kg of cholecalciferol) |
↓ serum level of vit. D3 ? ↑ Aβ deposition ? ↑ cognitive impairments ? |
[127] |
| Transgenic hemizygous 5xFAD mice | vitamin-D-deficient diet cholecalciferol (410 ng/g, i.p.) |
↑ Aβ production and deposits, astrogliosis, memory impairments- restored after cholecalciferol administration | [115] |
AChE—acetylcholinesterase; AD—Alzheimer’s Disease; Aβ—amyloid-beta peptide; BACE1—amyloid precursor protein cleaving enzyme-1; Bcl-2—family of regulator proteins that regulate cell death (apoptosis); Bax—pro-apoptotic Bcl-2 family member; BDNF—brain-derived neurotrophic factor; eNOS—endothelial nitric oxide synthase; ERK—extracellular signal-regulated kinase; GSH—gluthatione; GSK3β—serine⁄threonine protein kinase; HO-1—heme oxygenase 1; IL—interleukin; LPO—lipid peroxidation; LPS—lipopolysaccharide; LRP1—Low-density lipoprotein receptor-related protein 1; MDA—malondialdehyde; NF—κB-nuclear factor kappa-light-chain-enhancer of activated B cells; NGF—nerve growth factor; Nrf-2—nuclear-factor-erythroid-2-related factor 2; PGC-1α—transcriptional coactivator that regulates the genes involved in energy metabolism; SOD—superoxide dismutase; TAC—total antioxidant capacity; tau—microtubule-associated protein; TNFα—tumor necrosis factor alpha; TTG—total thiol groups; STZ—streptozotocin; UCMS—unpredictable chronic mild stress; VDR—the vitamin D receptor; ?—questionable data.