Immune and inflammatory interactions in Alzheimer's disease-related dementias

National Institute On Aging

Investigators

Linked publications & trials

Abstract

Using inter-laboratory funding we established the a-synuclein pre-formed fibril (PFF) injection model in the NIA/IRP and used it to evaluate the effect of age in the development of neuropathology, behavioral defects and the role of adaptive immunity. Additionally, we evaluated the status of microglial inflammation during disease progression. For this we injected PFF intra-striatally in matched cohorts of young and old mice obtained from the NIA aging colony and assayed the above characteristics at 1 and 3 months post-injection. During FY21 we accomplished the following: - We compiled the observations presented in the FY20 Annual report into a manuscript that was submitted for publication in late 2020. Though the reviews were very encouraging, several experiments were required for resubmission. The critical one was to carry out the study with a-synuclein monomers and pre-formed fibrils to ensure that the observed effects were due to a-synuclein aggregates. This experiment was carried out during the COVID-19 slowdown and all the data are now being repackaged in a revised manuscript that should be submitted by the end of september (2020). - we initiated experiments to study the effects of chronic low grade inflammation on the propagation of neuropathology in the 5xFAD mouse model of AD. - we carried out RNA-seq to determine the effects of age on microglia in 5xFAD mice. - we carried out anti-RelA ChIP-seq in BV2 microglial cells treated with LPS to identify sites of NF-kB recruitment in microglia. RNA prepared from these cells activated in the presence of IKK2 inhibitor BAY11-7082 is being analysed to identify genes whose expression is affected by blocking NF-kB. By combining genome-wide biding studies with gene expression studies we aim to identify direct and indirect targets of NF-kB in this cell type.