Dataset Information

Data in support of Anti-Aβ antibody treatment with Aducanumab modified the proteome of senile plaques and surrounding tissue and altered disease progression in a transgenic mouse model of Alzheimer’s disease.

ABSTRACT: Alzheimer’s disease (AD) is the most comment type of dementia and is characterized by neuronal loss and cognitive decline. Aggregation and accumulation of Aβ proteoforms into senile plaques (SP) is one of the key hallmarks of the disease. The accumulation of Aβ in particular in hippocampus has been observed prior to cognitive decline, indicating a potential link between Aβ and the subsequent pathological events in AD. Several clinical trials have used immunotherapies targeting Aβ for degradation but have had diverging outcome in AD patients. We therefore set to determine the molecular profile of SP and surrounding tissue following biologics based immunotherapy using two antibodies, gantenerumab and aducanumab, that have high binding affinity to different Aβ epitopes for investigating the antibody Aβ-clearing properties. We used two cohorts of the APPPS1-21 PD mouse model that overexpresses human mutated APP (KM670/671NL) and PSEN1 (L166P). After chronic treatment for 4-month with weekly dose (20 and 10 mg/kg gantenerumab or aducanumab, respectively), we investigated SP load in two brain regions using thioflavin-S staining. A significant reduction of SP was observed in hippocampus of aducanumab treated mice while only a partial reduction was observed in same region of gantenerumab treated mice compared to respective control (irrelevant IgG and vehicle (PBS) treated mice). To determine the molecular changes associated with the aducanumab treatment, we applied two mass spectrometry (MS) methods, matrix-assisted laser desorption-ionization (MALDI) imaging, and microproteomics by combining laser microdissection and liquid chromatography-tandem MS (LC-MS/MS). We microdissected three subregions, containing SP, SP penumbra (SPP1), and an additional penumbra (SPP2) to the SPP1 extract from the hippocampus of the treated mice.

INSTRUMENT(S): maXis

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Rheumatoid Arthritis Disease Specific Synovial Fluid

DISEASE(S): Alzheimer's Disease

SUBMITTER: Allan Stensballe

LAB HEAD: Allan Stensballe

PROVIDER: PXD021918 | Pride | 2021-03-25

REPOSITORIES: Pride

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Publications

Anti-Aβ Antibody Aducanumab Regulates the Proteome of Senile Plaques and Closely Surrounding Tissue in a Transgenic Mouse Model of Alzheimer's Disease.

Bastrup Joakim J Hansen Kathrine H KH Poulsen Thomas B G TBG Kastaniegaard Kenneth K Asuni Ayodeji A AA Christensen Søren S Belling Dorthe D Helboe Lone L Stensballe Allan A Volbracht Christiane C

Journal of Alzheimer's disease : JAD 20210101 1

<h4>Background</h4>Alzheimer's disease (AD) is characterized by accumulation of amyloid-β (Aβ) species and deposition of senile plaques (SPs). Clinical trials with the anti-Aβ antibody aducanumab have been completed recently.<h4>Objective</h4>To characterize the proteomic profile of SPs and surrounding tissue in a mouse model of AD in 10-month-old tgAPPPS1-21 mice after chronic treatment with aducanumab for four months with weekly dosing (10 mg/kg).<h4>Methods</h4>After observing significant red ...[more]

PMID: 33252074

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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:Alzheimer´s disease (AD) is the most common form of dementia. Over fifty years of intense research have revealed many key elements of the biology of this neurodegenerative disorder. However, our understanding of the molecular bases of the disease is still incomplete, and the available medical treatments for AD are mainly symptomatic and hardly effective. Indeed, the robustness of biological systems have revealed that the modulation of a single target is unlikely to yield the desired outcome, and we should move from gene-centric to systemic therapeutic strategies. Here, we present the complete characterization of three murine models of AD at different stages of the disease (i.e. onset, progression and advanced). To identify genotype-to-phenotype relationships, we combine the cognitive assessment of these mice with histological analyses and a full transcriptional and protein quantification profiling from hippocampus. Comparison between the gene and protein expression trends observed in AD progression and physiological ageing exposed certain commonalities, such as the upregulation of microglial and inflammation markers. However, although there is an accelerated ageing in AD models, there are other factors specifically associated with Aβ pathology. Despite the clear correlation between mRNA and protein levels of the dysregulated genes, we discovered a few proteins whose abundance increases with AD progression, while the corresponding transcript levels remain stable. Indeed, we show that at least two of these proteins, namely lfit3 and Syt11, co-localize with Aβ plaques in the brain. Finally, we derive specific Aβ-related molecular AD signatures, and we look for drugs able to globally revert them. We found two NSAIDs (dexketoprofen and etodolac) and two anti-hypertensives (penbutolol and bendroflumethiazide) that overturn the cognitive impairment in AD mice while reducing Aβ plaques in the hippocampus and partially restoring the physiological levels of AD signature genes to wild-type levels.

Project description:1,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (tetrahydrocurcumin, THC) is a major bioactive metabolite of curcumin (the principal active ingredient of Curcuma longa L.), and overcomes the low bioavailability of curcumin, demonstrating the potential anti-inflammatory, antioxidant and neuroprotective properties, etc, some of which were considered to be even superior to curcumin. In the present study, the protective properties of THC in the hippocampus of APP/PS1 mice, and the effects of THC against Aβ-induced toxicity in BV-2 cells were explored. The data in vitro showed that Aβ induced decreased cell viability, and cell cycle arrest and apoptosis in BV-2 cells, which could be ameliorated by THC. In vivo, THC administration was able to rescue learning and memory, and reduce Aβ burden in the hippocampus of APP/PS1 mice. By comprehensive proteomic analysis of the hippocampus of mice, a total of 157 differentially expressed proteins were identified in APP/PS1 mice treated with THC (comparing with APP/PS1 mice), which were enriched in “T cell activation”, “lymphocyte proliferation” and “protein oligomerization”, etc. The results of Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis suggested that the effects of THC on the cell cycle and apoptosis were mostly related to the “Ras signaling pathway” and “JAK−STAT signaling pathway”, etc. Using Western blot and ELISA, the down-regulation of Gab2 and K-Ras, and the up-regulation of caspase-3, TGF-β1 and TNF-ɑ were found in APP/PS1 mice. THC attenuated the abnormal expression of Gab2, K-Ras, caspase-3 and TNF-ɑ, and up-regulated Bag1 and TGF-β1 expression in APP/PS1 mice. In BV-2 cells, Aβ induced the down-regulation of Gab2, K-Ras and TGF-β1, and the overexpression of caspase-3, PARP1, cleaved-PARP1 and TNF-ɑ, which were markedly restored by THC. Moreover, THC up-regulated Bag1 expression in BV-2 cells treated with Aβ. The decreased transcriptional expression levels of Ccnd2 and Cdkn1a was also observed in Aβ-treated BV-2 cells. THC treatment alleviated down-regulation of Ccnd2, but did not affect the abnormal transcriptional expression of Cdkn1a caused by Aβ in BV-2 cells. For the first time, we identified that the action of THC in preventing AD was associated with inhibition of cell cycle arrest and apoptosis of microglia via the Ras/ERK signaling pathway, shedding new light on the role of THC in alleviating the progression of AD.

Dataset Information

Data in support of Anti-Aβ antibody treatment with Aducanumab modified the proteome of senile plaques and surrounding tissue and altered disease progression in a transgenic mouse model of Alzheimer’s disease.

Publications

Anti-Aβ Antibody Aducanumab Regulates the Proteome of Senile Plaques and Closely Surrounding Tissue in a Transgenic Mouse Model of Alzheimer's Disease.

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