Age-related changes in hippocampal AD pathology, actin remodeling proteins and spatial memory behavior of male APP/PS1 mice.

Alzheimer's disease (AD) is the most common form of dementia in the elderly, characterized by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles (NFTs). Synaptic plasticity impairment is one of the early pathological events in AD. Transgenic APP/PS1 mice that overproduce Aβ are one of the most extensively used AD animal models. Many studies have investigated the roles of NTF-related p-Tau, non-amyloidogenic ADAM10, amyloidogenic BACE1, Aβ proteolytic NEP and IDE in certain ages of APP/PS1 mice as well as dendritic spine-related Rictor and Profilin-1 in normal mice, but there are few studies exploring the age-related changes of these molecules in the hippocampus of APP/PS1 mice. Furthermore, current studies regarding when memory impairment occurs in these mice are controversial. Thus, we examined the changes of these molecules in APP/PS1 and control mice using Western blot in mice 2-month-old (2 m) to 10 m of age and behavior changes using the Morris water maze from 4 m to 8 m. The results showed that in APP/PS1 mice, significant changes of hippocampal p-Tau, Aβ, ADAM10, BACE1 and Rictor occurred at 6 m, NEP at 8 m, and IDE and Profilin-1 at 10 m. In control mice, changes of p-Tau, ADAM10, and BACE1 occurred at 8 m and NEP at 10 m, while IDE, Rictor and Profilin-1 remained unchanged. Importantly, the Morris water maze test revealed that spatial memory impairment was detected at 8 m but not 4 or 6 m. The above findings clearly evidence that neurochemical changes overtly precede cognitive dysfunctions in this AD model and provide novel knowledge for a better understanding of the molecular events driving AD.

Sun H ，Liu M ，Sun T ，Chen Y ，Lan Z ，Lian B ，Zhao C ，Liu Z ，Zhang J ，Liu Y ... -  《-》

Hippocampal overexpression of SGK1 ameliorates spatial memory, rescues Aβ pathology and actin cytoskeleton polymerization in middle-aged APP/PS1 mice.

The increasing occurrence and ineffective treatment of Alzheimer's disease (AD) has become one of the major challenges of the world. Limited studies have shown that serum- and glucocorticoid-inducible kinase 1 (SGK1) is involved in spatial memory formation and consolidation, but its role in AD-like spatial memory impairment and the related mechanisms are not clear. In this study, we first examined the age-related changes of SGK1 in the hippocampus of female APP/PS1 (AD) mice. Based on the finding and our previous finding that significant spatial memory impairment was detected in 8-month old AD mice, SGK1-overexpressing AAV (oSGK1) was constructed and injected into the hippocampus of 9-month old AD mice. One month later, the behavior alterations, Aβ production and deposit as well as changes of CA1 spine density and selected actin polymerization remodeling proteins were examined. The results showed that significant decrease of SGK1 was detected in 10-month old AD mice. The spatial memory impairment, the production and deposit of Aβ were reversed by oSGK1. Levels of hippocampal ADAM10 (α-secretase) and IDE (Aβ degradase), actin remodeling related proteins Rictor, Rac1, Cdc42 and Profilin-1 were significantly increased after oSGK1 treatment while hippocampal BACE1 (γ-secretase) and Cofilin remained unchanged. Taken together, our findings demonstrated a pivotal role of SGK1 in the treatment of AD-related memory impairment through upregulation of non- amyloidogenic processing of APP and degradation of Aβ, increase in spine plasticity related proteins, indicating increase in hippocampal SGK1 may be a potent therapeutic target against AD.

Lian B ，Liu M ，Lan Z ，Sun T ，Meng Z ，Chang Q ，Liu Z ，Zhang J ，Zhao C ... -  《-》

GEPT extract reduces Abeta deposition by regulating the balance between production and degradation of Abeta in APPV717I transgenic mice.

Tian J ，Shi J ，Zhang L ，Yin J ，Hu Q ，Xu Y ，Sheng S ，Wang P ，Ren Y ，Wang R ，Wang Y ... -  《-》

27-hydroxycholesterol promotes Aβ accumulation via altering Aβ metabolism in mild cognitive impairment patients and APP/PS1 mice.

The oxysterol 27-hydroxycholesterol (27-OHC) has been considered to play a key role in the pathogenesis of Alzheimer's disease (AD). Because β-amyloid peptide (Aβ) is the pathological hallmark of AD, the aim of this study is to verify whether 27-OHC could lead to cognitive impairment through modulating Aβ accumulation and deposition. Regulation of Aβ metabolism was explored as the pathogenic mechanism of 27-OHC. Furthermore, microRNAs (miRNAs) and their relations with 27-OHC were also detected. In present study, matched case-control study and APP/PS1 transgenic mice research were conducted. The results showed that the 27-OHC and Aβ in plasma were increased in mild cognitive impairment patients, and a slight correlation was found between 27-OHC and Aβ1-40. This relationship was also proved by the research of APP/PS1 mice. More severe learning and memory impairment and higher Aβ1-40 expression in brain and plasma were detected in the APP/PS1 mice of 27-OHC treatment group. In addition, increased amyloid plaques were also found in the hippocampus of 27-OHC-treated mice. In order to find out the mechanism of 27-OHC on regulating Aβ metabolism, the factors of Aβ production (APP, BACE1 and ADAM10), transport (LRP1 and RAGE) and elimination (NEP and IDE) were tested respectively. The gene and protein expressions of APP, BACE1 and RAGE were increased while LRP1 and IDE were decreased in the brain of 27-OHC-treated mice. At last, down-regulated expression of miRNA let-7g-5p was found after 27-OHC treatment. In conclusion, these findings suggested that excessive 27-OHC could enhance the accumulation and deposition of Aβ both in brain and blood, resulting in a severe impairment of cognition, especially in the modulation of Aβ1-40. The mechanism might be associated with the regulation of Aβ metabolism, and miRNA let-7g-5p was likely to play a vital role in this pathological process induced by 27-OHC.

Zhang X ，Xi Y ，Yu H ，An Y ，Wang Y ，Tao L ，Wang Y ，Liu W ，Wang T ，Xiao R ... -  《-》

CART modulates beta-amyloid metabolism-associated enzymes and attenuates memory deficits in APP/PS1 mice.

Yin K ，Jin J ，Zhu X ，Yu L ，Wang S ，Qian L ，Han L ，Xu Y ... -  《-》