Project description:Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. So far, there is no effective treatment for this condition. Tetramethylpyrazine (TMP) is an alkaloid extracted from traditional Chinese medicine chuanxiong, which is mainly used in the treatment of ischemic stroke some related diseases. In this study, we studied the potential effects of TMP on AD progression by using two AD mouse models. 8-month-old 3xTg-AD mice received TMP treatment (10mg/kg/d) for 1 month, and 4-month-old APP/PS1-AD mice received TMP treatment (10mg/kg/d) for 2 months. The behavioral tests by step-down passive avoidance test (SDA), new object recognition (NOR) and Morris water maze (MWM) showed that TMP significantly improved the learning and memory impairment of two AD transgenic mice. In addition, TMP reduced Aß levels and tau phosphorylation. Venny analysis showed that 116 differentially expressed proteins were commonly changed in 3xTg mice vs WT mice and TMP treated mice vs untreated mice. The same, 130 differentially expressed proteins were commonly changed in APP/PS1 mice vs WT mice and TMP treated mice vs untreated mice. The functions of the common proteins modified by TMP in the two models were mainly related to mitochondrial function, synaptic function, cytoskeleton, GTP binding, ATP binding. Mitochondrial omics analysis revealed 21 and 20 differentially expressed mitochondrial proteins modified by TMP in 3xTg-AD mice and APP/PS1 mice, respectively. These differential proteins were located in mitochondrial inner membrane, mitochondrial outer membrane, mitochondrial gap and mitochondrial matrix, and the function of some proteins is closely related to oxidative phosphorylation of (OXPHOS). Western-blot further validated that TMP changed the expression of OXPHOS complex proteins (sdhb, ndufa10, uqcrfs1, cox5b, atp5a) in the hippocampus of the two AD mice. Taken together, our study demonstrated that TMP improved the cognitive impairment and AD-like pathology, and modified hippocampal proteome in the two AD mice models. The improvement of the behavioral and pathology might be associated with modification of mitochondrial protein profile by TMP. Our study suggested that TMP had the potential for the treatment of AD.

Project description:Alzheimer’s disease (AD) is a chronic ageing related neurodegenerative disease which is characterized by loss of synapses and neurons in the vulnerable brain regions. Expression perturbations of amyloid β (Aβ) and tau protein in the brain are two hallmarks of AD. Aβ is abnormally generated from amyloid precursor protein (APP) which is broadly distributed in different brain regions including the hippocampus and cortex. It is believed that increased Aβ expression plays a causative role in the early stage of AD pathology. Aβ protein interacts with the signaling pathways that control the phosphorylation of the microtubule-associated protein tau, which eventually disrupts the neuronal circuitry as well as network connectivity leading to neurodegenerative processes observed in AD. In addition, substantial molecular and neurodegenerative changes occur in the initial stage of AD even before the cognitive symptoms are evident, which makes the early diagnosis of AD vital to any timely disease stabilization and treatment. However, despite myriad efforts and substantial progress in the field to decipher the molecular mechanisms of disease onset and its progression, specific causes underlying AD pathology remain ill-defined. There is an urgent need to identify novel mechanism based interventional approaches that can stop, or slow down, the progression of AD. Therefore, it is important to improve the knowledge of the early AD and have a better understanding of the underlying molecular mechanisms induced by Aβ. In this study, we performed comparative quantitative proteomics on different brain regions of 2.5 months old APP/PS1 mice (hippocampus, frontal cortex, parietal cortex and cerebellum) in order to investigate the early stage impact of AD. Although over 5000 proteins were identified in all regions, the proteome response across regions was greatly varied. As expected, the greatest proteome perturbation was detected in the hippocampus and frontal cortex (AD-susceptible brain regions), compared to only 155 changed proteins in the cerebellum (less vulnerable region to AD). Increased expression of APP protein was identified in all brain regions. The expression of the majority of the other proteins between hippocampus and cortex areas was not similar, highlighting differential effects of the disease on different brain regions. A series of AD associated markers and pathways were identified as overexpressed in the hippocampus including glutamatergic synapse, GABAergic synapse, retrograde endocannabinoid signaling, long-term potentiation, and calcium signaling. In contrast, the expression of same proteins and pathways was negatively regulated in frontal and parietal cortex regions. Additionally, an increased expression of proteins associated with the oxidative phosphorylation pathway in hippocampus was not evident in the two cortices. Interestingly, an increased expression of proteins involved with myelination, neurofilament cytoskeleton organization, and glutathione metabolism was identified in cortex areas, while these were reduced in the hippocampus. The results obtained from this study highlight important information on brain region specific protein expression changes occurring in the early stages of AD.

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Rapamycin regulate cholesterol metabolism and ribosomal proteins in Alzheimer’s disease

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Rapamycin regulates cholesterol biosynthesis and cytoplasmic ribosomal proteins in hippocampus and temporal lobe of APP/PS1 mouse.

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