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.

Project description:Information about the genes that are preferentially expressed during the course of Alzheimer’s disease (AD) could improve our understanding of the molecular mechanisms involved in the pathogenesis of this common cause of cognitive impairment in older persons, provide new opportunities in the diagnosis, early detection, and tracking of this disorder, and provide novel targets for the discovery of interventions to treat and prevent this disorder. Information about the genes that are preferentially expressed in relationship to normal neurological aging could provide new information about the molecular mechanisms that are involved in normal age-related cognitive decline and a host of age-related neurological disorders, and they could provide novel targets for the discovery of interventions to mitigate some of these deleterious effects. Aim 1. Collect brain samples from three Alzheimer’s Disease Centers (ADCs) for subsequent gene expression profiling. Individuals will be stratified with respect to diagnostic groups (using both clinical and neuropathological criteria), age groups, and APOE genotype. 150 individual brains will be sampled from the Arizona ADC, the Duke University ADC, and the Washington University ADC. Miniscule sample sizes (200 um of sectioned tissue) from six brain regions that are histopathologically or metabolically relevant to AD and aging will be collected, ensuring that this proposal does not deplete the national resource. Frozen and fixed samples will be sent to Phoenix, sectioned in a standardized fashion, and then returned. Aim 2. Tissue heterogeneity will be eliminated prior to expression profiling by performing laser capture microscopy on all brain regions. Aim 3. Expression profile LCM-captured cells on the Affymetrix U133 Plus 2.0 array (~55,000 transcripts), and quickly provide these data to the community at large. Aim 4. Identify pathogenic cascades related to each of the clinico-pathologic correlates using unsupervised and supervised analyses coupled with a hypothesis-driven approach. Aim 5. Validation of the expression correlates at the protein and functional levels. Scientific progress in the last few years has improved our understanding of AD and raised the hope of identifying treatments to halt the progression and prevent the onset of this disorder. For instance, researchers have begun to characterize the cascade of molecular events which lead to the major histopathological features of the disorder: neuritic plaques, which contain extra-cellular deposits of amyloid beta-peptides (Abeta); neurofibrillary tangles, which contain the hyperphosphorylated form of the intracellular, microtubule-associated protein, tau; and a loss of neurons and synapses. These molecular events provide targets for the development of promising new treatments. For example, A-beta has been postulated to trigger a cascade of events that are involved in the pathogenesis of AD. This proposal hopes to provide new information about the genes that are preferentially expressed in the development of AD histopathology, including the over-expression of APP, amyloid-induced neurotoxicity, and hyperphosphorylation of tau, as well as bring clarity to the metabolic abnormalities that seem to play a role in dementia and AD development and pathology. We will perform LCM on 6 brain regions with about 14 biological replicates per brain region. The brain regions are as follows: 1) entorhinal cortex 2) hippocampus 3) medial temporal gyrus 4) posterior cingulate 5) superior frontal gyrus and 6) primary visual cortex. We will collect layer III pyramidal cells from the white matter in each region, isolate total RNA from LCMed cell lysates, and perform double round amplification of each sample for array analysis. Keywords: other

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Human brain Alzheimer's - Proteomic signatures of brain regions affected by tau pathology in early and late stages of Alzheimer's disease

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Proteomic signatures of brain regions affected by tau pathology in early and late stages of Alzheimer's disease.

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