Korean J Physiol Pharmacol.  2020 Jan;24(1):39-46. 10.4196/kjpp.2020.24.1.39.

β-Sitosterol treatment attenuates cognitive deficits and prevents amyloid plaque deposition in amyloid protein precursor/presenilin 1 mice

• Ye JY
• Li L
• Hao QM
• Qin Y
• Ma CS

• KMID: 2466568
• DOI: http://doi.org/10.4196/kjpp.2020.24.1.39

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder causing dementia worldwide, and is mainly characterized by aggregated β-amyloid (Aβ). Increasing evidence has shown that plant extracts have the potential to delay AD development. The plant sterol β-Sitosterol has a potential role in inhibiting the production of platelet Aβ, suggesting that it may be useful for AD prevention. In the present study, we aimed to investigate the effect and mechanism of β-Sitosterol on deficits in learning and memory in amyloid protein precursor/presenilin 1 (APP/PS1) double transgenic mice. APP/PS1 mice were treated with β-Sitosterol for four weeks, from the age of seven months. Brain Aβ metabolism was evaluated using ELISA and Western blotting. We found that β-Sitosterol treatment can improve spatial learning and recognition memory ability, and reduce plaque load in APP/PS1 mice. β-Sitosterol treatment helped reverse dendritic spine loss in APP/PS1 mice and reversed the decreased hippocampal neuron miniature excitatory postsynaptic current frequency. Our research helps to explain and support the neuroprotective effect of β-Sitosterol, which may offer a novel pharmaceutical agent for the treatment of AD. Taken together, these findings suggest that β-Sitosterol ameliorates memory and learning impairment in APP/PS1 mice and possibly decreases Aβ deposition.

Keyword

Alzheimer disease; Amyloid-beta; β-Sitosterol; Learning and memory

MeSH Terms

Alzheimer Disease
Amyloid*
Animals
Blood Platelets
Blotting, Western
Brain
Cognition Disorders*
Dementia
Dendritic Spines
Enzyme-Linked Immunosorbent Assay
Excitatory Postsynaptic Potentials
Learning
Memory
Metabolism
Mice*
Mice, Transgenic
Neurodegenerative Diseases
Neurons
Neuroprotective Agents
Plant Extracts
Plants
Plaque, Amyloid*
Spatial Learning
Amyloid
Neuroprotective Agents
Plant Extracts

Figure

• 

  Fig. 1 β-Sitosterol treatment attenuates spatial learning and recognition memory deficits in amyloid protein precursor/presenilin 1 (APP/PS1) mice. (A) The escape latency of APP/PS1 mice in the navigation test. (B) The percentage of time spent in the target quadrant of APP/PS1 mice in the probe test. (C) The number of target platform crossings of APP/PS1 mice in the probe test. (D) Recognition preference for novel object of wild-type (WT) mice. (E) Recognition preference for novel object in control APP/PS1 mice. (F) Recognition preference for novel object in β-Sitosterol treated APP/PS1 mice. (G) Statistical results of recognition difference scores for novel object in β-Sitosterol treated APP/PS1 mice. Data are presented as mean ± standard error of the mean, n = 10–12 mice per group, gender mixed. One-way ANOVA, Bonferroni multiple comparisons test or Student's t-test were used: ##p < 0.01, ###p < 0.001, **p < 0.01.

• 

  Fig. 2 Analysis of β-amyloid (Aβ) metabolism in β-Sitosterol treated amyloid protein precursor/presenilin 1 (APP/PS1) mice. (A, B) ELISA of soluble Aβ40 and Aβ42 in hippocampal and cortical samples of APP/PS1 mice. (C, D) ELISA of insoluble Aβ40 and Aβ42 in hippocampal and cortical samples of APP/PS1 mice. Data are presented as mean ± standard error of the mean. n = 9–12 mice per group, gender mixed. One-way ANOVA, Bonferroni multiple comparisons test or Student's t-test were used: ###p < 0.001 vs. wild-type (WT), **p ≤ 0.001 vs. APP/PS1 mice.

• 

  Fig. 3 β-Sitosterol treatment attenuated β-amyloid (Aβ) and BACE1 protein expression in amyloid protein precursor/presenilin 1 (APP/PS1) mice. (A) Aβ staining of the hippocampus and cortex of APP/PS1 mice (×40). (B) The Aβ density values are expressed in arbitrary units. (C) Immunoblot semi-quantitative analysis of Aβ and BACE1 protein expression in the hippocampus of APP/PS1 mice. Data are presented as mean ± standard error of the mean. n = 12–16 mice per group, gender mixed. One-way ANOVA, Bonferroni multiple comparisons test or Student's t-test were used: ###p < 0.001 vs. wild-type (WT), **p ≤ 0.001 vs. APP/PS1 mice.

• 

  Fig. 4 β-Sitosterol treatment restored synaptic dysfunction in amyloid protein precursor/presenilin 1 (APP/PS1) mice. (A) Confocal images of green fluorescent protein-labeled-hippocampal neurons were used to visualized the dendritic spines. 6–8 field per animal, 7–8 animals per group. (B) Representative traces of miniature excitatory postsynaptic currents (mEPSCs) recorded in hippocampal neurons of each group. (C, D) Statistical analyses of the mean values of mEPSC frequencies and amplitudes in hippocampal neurons of each group. Data are presented as mean ± standard error of the mean. n = 9–12 mice per group, gender mixed. One-way ANOVA, Bonferroni multiple comparisons test or Student's t-test were used: ###p < 0.001 vs. wild-type (WT), **p ≤ 0.001 vs. APP/PS1 mice.

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