The identification of the cell type-specific expression and activation of NF-kappaB, Sp1 and YY1 transcription factors may provide a basis to specifically interfere with BACE1 expression and, thereby, to lower the concentrations of beta-amyloid peptides, which may prevent neuronal cell loss and cognitive decline in AD patients.
This is because BACE1 catalyses the rate limiting step in the production of amyloid-beta (Abeta) the principal component of plaque pathology in AD, the excessive production of which is believed to be a primary cause of neurodegeneration, and cognitive dysfunction in AD.
We have recently shown that Alzheimer's disease (AD) transgenic mice given a moderate level of caffeine intake (the human equivalent of 5 cups of coffee per day) are protected from development of otherwise certain cognitive impairment and have decreased hippocampal amyloid-beta (Abeta) levels due to suppression of both beta-secretase (BACE1) and presenilin 1 (PS1)/gamma-secretase expression.
Genetic targeting aromatase in male amyloid precursor protein transgenic mice down-regulates beta-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment.
We demonstrate that genetic reductions of both BACE1 and gamma-secretase additively attenuate the amyloid burden and ameliorate cognitive deficits occurring in aged APPswe/PS1DeltaE9 animals.
In this study, we used heterozygous BACE1 gene knockout (BACE1+/-) mice to evaluate the effects of partial BACE1 suppression on different types of synaptic and cognitive dysfunctions in Alzheimer's transgenic mice (5XFAD model).
Previous studies have demonstrated that chronic brain hypoperfusion (CBH) causes Aβ aggregation by upregulating expression of amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 (BACE1) protein, which is accompanied by cognitive impairment, but the mechanisms are not fully understood.
These results indicate that DISC1 attenuates Aβ generation and cognitive deficits of APP/PS1 transgenic mice through promoting lysosomal degradation of BACE1.
These data highlight the potential benefits of BACE inhibition for the effective treatment of a wide range of AD-like pathophysiological and cognitive impairments.
Surprisingly, blocking GRs for only 3 days at 12 months of age reduced CORT levels, reduced hippocampal Aβ40 and -42, and β-site APP-cleaving enzyme 1 (BACE1) levels, and notably rescued the cognitive deficits in 12-month-old APPswe/PS1dE9 mice.
The senile plaques (SPs) in the brain are one of the most pathophysiological characteristics of cognitive dysfunction and its major constituent amyloid β (Aβ) released from amyloid precursor protein (APP) by β (BACE1) and γ (presenilin 1) secretases .
However, so far pharmacological BACE1 inhibition failed to rescue the cognitive decline in mild-to-moderate AD patients, which indicates that treatment at the symptomatic stage might be too late.
Previous studies indicated that BACE1 initially cleaves the amyloid precursor protein (APP) and may subsequently interfere with physiological functions of proteins such as PKA, which is recognized to be closely associated with long-term potentiation (LTP) level and can effectively ameliorate cognitive impairments.
Using this system to target Bace1 suppressed amyloid beta (Aβ)-associated pathologies and cognitive deficits in two mouse models of Alzheimer's disease.
It has been hypothesised that partial inhibition of BACE1 in individuals with a high risk of developing Alzheimer's disease may be beneficial in preventing cognitive decline.