Additional Table 1.
Pathophysiological and behavioral outcomes of SSRIs in AD animal models
| SSRI | Study | Animal model/age at baseline/sex | Dose | Duration of treatment | Outcomes (P-values reported vs. placebo) | |
|---|---|---|---|---|---|---|
| Pathophysiological | Behavioral | |||||
| Citalopram | Zhang et al. (2018) | APP/PS1/6 months old/male | 10 mg/kg per day | 28 days | Reduced Aβ deposition in cortex (P < 0.001) and hippocampus (P < 0.05). | Reversed impaired short-term memory. |
| Inhibited microgliosis in cortex (P < 0.01) and hippocampus (P < 0.05) (ameliorated lba1+). | Ameliorated sociability but no effect on social recognition. | |||||
| Increased PV labeled neurons in cortex (P < 0.001) but not in hippocampus. | Ameliorated impaired nesting behaviors. | |||||
| Reversed repetitive behaviors. | ||||||
| Improved depressive-like behaviors. | ||||||
| Wei et al. (2017) | 3xTgAD/5 months old/female | 10 mg/kg per day | 3 months | Decreased hippocampal levels of APP in post hoc analysis (P = 0.001) | Did not improve locomotion and anxiety-like behaviors. | |
| Decreased cortical and hippocampal levels of insoluble Aβ40 (P < 0.018 and P < 0.035 respectively) but not Aβ42 (P = 0.923 and P = 0.91 respectively) | No significant effect on depression-like behavior. | |||||
| Reversed hippocampal LTP impairment (P < 0.047). | Reversed spatial learning ability (P < 0.05). | |||||
| Improved spatial memory (P < 0.003). | ||||||
| Citalopram | Sheline et al. (2014b) | APP/PS1/12 months old/male and female | 2.5, 5, 10, 20 mg/kg | 24 hours | Dose dependent reduction in brain ISF Aβ levels with 5 mg (12.4%) and 10 mg (24.5%) (no significant change at 2.5 mg nor at 20 mg). | – |
| APP/PS1/6 months old/male and female | 10 mg/kg per day | 28 days | Reduction of likelihood of plaque growth [OR = 0.30 (0.15–0.60), P = 0.0008]. Reduction of newly appearing plaques (P = 0.01). No effect on clearing already formed plaques (P = 0.93). Reduction of amyloid angiopathy progression (P = 0.03). |
– | ||
| Cirrito et al. (2011) | APP/PS1/2–3 months old/male and female | 5 and 10 mg/kg | 12–24 hours | Dose dependent reduction of ISF Aβx-40 (16% for 5 mg and 24% for 10 mg). Reduction in ISF Aβx-40 and Aβx-42 to 71.9 ± 9.4% and 66.7 ± 16.3% of baseline respectively with the 10 mg dose. No effect on clearance of ISF Aβ. Activation of pERK2 and pMEK1/2. Increased α-secretase activity in the hippocampus by 25% (P = 0.01) with no effect on β-secretase. |
– | |
| Citalopram | Cirrito et al. (2011) | APP/PS1/3 months old/female | 8 mg/kg per day | 4 months | Reduced cortical and hippocampal plaque burden (by 62% and 55% respectively). Reduced CSF Aβ40 and Aβ42 levels (by 28 and 55% respectively). Significantly higher reduction of Aβ42 vs. Aβ40 (P = 0.0004). Increased α-secretase activity (P < 0.001) Unchanged β and γ secretase activity. |
– |
| APP/PS1/12 months old/female | 10 mg/kg per day | 8 months | Reduced ISF Aβ40 levels by 25% (P = 0.008). | – | ||
| Fluoxetine | Zhou et al. (2019) | APP/PS1/8 months old/male | 10 mg/kg per day | 10 weeks | Decreased levels of soluble Aβ40 (P = 0.001) and Aβ42 (P = 0.000) in the hippocampus. Reduced amyloid plaques in DG (P = 0.000) and CA1/2 (P = 0.006) regions of the hippocampus but no significant changes in CA3. Delayed dendritic-spine synapse loss in DG (P = 0.001), CA1/2 (P = 0.006), and CA3 (P = 0.025) of the hippocampus. |
Improved learning ability. |
| Sun et al. (2017) | 3xTgAD/35 days old/male | 10 mg/kg | 15 days (measurements done at 6 months old) | Significant reduction of Aβ levels in the hippocampus (DG, CA1) and cortex, but no change in levels of phosphorylated tau proteins. Increased levels of synaptic proteins: GluN2B, GluA1, GluA2, PSD93 and PSD95. Increased expression of CREB (P < 0.01)/BDNF (P < 0.001). Enhancement of hippocampal LTP (P < 0.001). Increased number of neurons and spine density in hippocampus and cortex (P < 0.001). Increased size of multiple brain areas (caudate, putamen, amygdala, hypothalamus, CA1, DG, insula, pisiform/parietal/occipital cortex). | Preserved learning and memory abilities. Preventive effect on cognitive functions. | |
| Fluoxetine | Ma et al. (2017) | APP/PS1/16–17 months old/male | 10 mg/kg per day | 5 weeks | Decreased Aβ amyloid in hippocampus Prevented neuronal loss in hippocampal DG (P < 0.05) but not in CA1 or CA3 (P > 0.05). | Improved spatial learning ability (P < 0.05). |
| Promoted neurogenesis through activation of β-catenin (P < 0.05) and inhibition of GSK3β. | No improvement in spatial memory (P > 0.05). | |||||
| Jin et al. (2017) | 3xTgAD/6 months old/male | 1 mg/100 g | 15 days | Decreased Aβ levels in the hippocampus but no effect on tau proteins. | Improved learning and memory abilities (P < 0.05). | |
| Increased expression of synaptic proteins in hippocampus promoting neurogenesis. | ||||||
| Activation of CREB/p-CREB/BDNF pathway in hippocampus. | ||||||
| Increased neuronal area and dendritic spines density in hippocampal CA1 and DG regions. | ||||||
| Enhanced synaptic plasticity/LTP (P < 0.001). | ||||||
| Restored brain volume loss mainly at CA1 and DG (P < 0.005). | ||||||
| Fluoxetine | Qiao et al. (2016) | APP and PS1/2 months old/male and female | 5 mg/kg per day | 4 months | Decreased generation of soluble Aβ40 and Aβ42 from astrocytes via their 5HT2 receptors (P < 0.05). | Improved short term spatial memory |
| Prevented neuronal damage by preventing decrease in dendritic complexity and axonal branching (P < 0.05). | Improved spatial memory and impaired behavioral performance. | |||||
| Prevented increase/accumulation of activated astrocytes. | ||||||
| Reduction in area fraction and number of amyloid plaques per area (P < 0.05). | ||||||
| Wang et al. (2016) | Primary cultures of hippocampal neurons of fetal brains (embryonic day 18) obtained from female Sprague-Dawley rats; and treated with Aβ1–42 | – | – | Decreased Aβ1–42-induced tau hyperphosphorylation in a concentration-dependent manner. Increased Tau-1 (unphosphorylated tau) No effect on Tau-5 (total tau). | – | |
| Fluoxetine | Wang et al. (2014) | APP/PS1/2 months old/male and female | 2.5, 5 mg/kg per day | 7 months | Decreased levels of soluble Aβ40 in the brain (P < 0.01), blood (P < 0.05) and CSF (P < 0.05). | Dose-dependent behavioral changes with the 5 mg but not 2.5 mg. |
| Decreased levels of soluble Aβ42 in the brain (P < 0.05), blood (P < 0.05) and CSF (P < 0.05). | Prevented impairment in short-term spatial memory, memory acquisition and retention. | |||||
| Inhibition of APP phosphorylation with no action on β-secretase (BACE-1). | Prevented decrease in locomotion and anxiety-like behaviors. | |||||
| Prevented loss of MAP2 and SYP in the cortex. | ||||||
| No effect on amyloid deposition in brain (no significant difference in number and area fraction of amyloid plaques). | ||||||
| Cirrito et al. (2011) | APP/PS1/2–3 months old/male and female | 10 mg/kg | 12–24 hours | Reduction in ISF Aβx-40 levels to 73.4 ± 2.0% (P < 0.0001). | – | |
| Ivković et al. (2004) | NBM-lesioned rats/adults/male | 3, 5, 10 mg/kg | 7 days | – | Improved memory and learning in 40.1% of 5 mg fluoxetine treated rats compared to 20.2% untreated rats (P < 0.001) and 20.1% of rats treated with 3 or 10 mg fluoxetine (P < 0.05) (dose-independent effect). | |
| Paroxetine | Severino et al. (2018) | APP/PS1/9 months old/male | 5, 10 mg/kg per day | 3 months | No difference in plaque load (P > 0.05) | – |
| No effect on Aβ40, Aβ42 cortical levels nor Aβ42/Aβ40 ratio (P > 0.05). | ||||||
| 9 months | No change in plaque load, density and size in the cortex. | Increased risk of premature death even with the 5 mg/kg per day dosing (P < 0.001). | ||||
| No effect on behaviors and social interaction with the 5 mg/kg per day dosing. | ||||||
| Olesen et al. (2017) | APP/PS1/9 months old/male | 30, 10, 5 mg/kg per day | 9 months | No effect on the number of granular neurons or the number of DCX+ neuroblasts in the hippocampus. | No effect on spatial working memory. | |
| Reduction of Aβ plaque load in the hippocampus by 40% (P < 0.01). | ||||||
| Olesen et al. (2016) | APP/PS1/9 months old/male | 30, 10, 5 mg/kg per day | 3, 6, 9 months | No effect on Aβ plaque load in neocortex (P = 0.71) and no correlation between Aβ load and change in behavior. | Increased level of explorative and risk assessment behavior starting 15 months of age. | |
| No change in locomotor or anxiety-like behaviors. | ||||||
| No change in social interaction. | ||||||
| Paroxetine | Nelson et al. (2007) | 3xTg AD/5 months old/male and female | 5 mg/kg per day | 5 months | Reduced cortical levels of amyloid Aβ1–40 by > 50% in both males and females (P < 0.05) but no significant effects on Aβ1–42 (using ELISA method). | No significant effect on spontaneous exploratory activity or transfer latency. |
| Decreased Aβ immunoreactivity in hippocampus and cerebral cortex. | Improved memory acquisition without affecting retention. | |||||
| Reduced tau immunoreactivity in CA1 hippocampal and amygdala neurons in males but not in females that already had lower tau levels prior to treatment. | ||||||
| Escitalopram | von Linstow et al. (2017) | APP/PS1/3 months old/male and female | 5 mg/kg per day | 6 months | No effect on CSF levels of Aβ40 and Aβ42 Increased levels of Aβ40 in the neocortex (P < 0.05). Tendency towards increased Aβ42 levels in the cortex (P = 0.089). No effect on Aβ40 levels but tendency towards reduction of Aβ42 in the hippocampus (P = 0.11). No effect on the processing of APP (no change in soluble APPα levels in neocortex and hippocampus). | |
| Wang et al. (2016) | Primary cultures of hippocampal neurons of fetal brains (embryonic day 18) obtained from female Sprague-Dawley rats; and treated with Aβ1–42 | – | – | Decreased Aβ1–42-induced tau hyperphosphorylation in a concentration-dependent manner, through the 5-HT1A receptor mediated activation of the PI3K/Akt/GSK-3β pathway. No effect on Tau-5 that represents the total tau protein. Upregulation of the dendritic density and the total length of primary dendrites decreased by Aβ1–42. | – | |
APP/PS1: Amyloid precursor protein/presenilin-1 transgenic mouse; Aβ: amyloid-β peptide; Iba1+: ionized calcium binding adaptor molecule 1 positive (microglia/macrophage-specific calcium-binding protein); PV: parvalbumin; 3xTgAD: Triple transgenic model of Alzheimer’s disease mice (expressing the PS1m146v, APPswe and TauP301L mutations); APP: amyloid precursor protein; Aβ40: amyloid-β peptide 40; Aβ42: amyloid-β peptide 42; LTP: long term potentiation; ISF: interstitial fluid; OR: odds ratio; pERK2: phosphorylated extracellular regulated kinase 2; pMEK1/2: phosphorylated MAPK (mitogen-activated protein kinase) kinase 1/2; α-secretase: alpha secretase; β-secretase: beta secretase; CSF: corticospinal fluid; γ-secretase: gamma secretase; 5-HT1A: 5-hydroxy tryptophan 1 A; PI3K/Akt/GSK-3β: phosphatidylinositol-3-kinase/ protein kinase b/glycogen synthetase 3 β; Tau5: Tau protein 5; DG: dentate gyrus; CA1/2: cornu ammonis 1/2 of hippocampus; CA3: cornu ammonis 3 of hippocampus; GluN2B: N-methyl D-aspartate receptor subtype 2B; GluA1: AMPA-selective glutamate receptor 1; GluA2: N-methyl D-aspartate receptor subtype 2A; PSD93: postsynaptic density protein 93; PSD95: postsynaptic density protein 95; β-catenin: beta catenin; CREB: cyclic adenosine monophosphate response element binding; BDNF: brain derived neurotrophic factor; p-CREB: phosphorylated cyclic AMP response element binding; 5HT2: 5-hydroxy tryptophan 2; BACE-1: β-site amyloid precursor protein cleaving enzyme 1; MAP2: microtubule associated protein 2; SYP: synaptophysin; NBM: nucleus basalis of meynert; DCX+: doublecortin-positive; ELISA: enzyme-linked immunosorbent assay.