Identification and Quantitation of Novel Isoforms Relative to Alzheimer's Disease Genetics and Neuropathology.

Elucidating the actions of genetic polymorphisms associated with the risk of Alzheimer's disease (AD) may provide novel insights into underlying mechanisms. Two polymorphisms have implicated as a modulator of AD risk. Here, we sought to identify isoforms expressed in human AD and non-AD brain, quantify the more abundant isoforms as a function of AD genetics and neuropathology, and provide an initial in vitro characterization of the proteins produced by these novel isoforms. We report that expression is increased with AD neuropathology but not associated with AD genetics. Single-cell RNAseq of APP/PS1 mice showed that is primarily expressed by microglia, including disease-associated microglia. In human brain, several novel isoforms were identified, including isoforms with partial or complete loss of exon 6. Expression of these isoforms correlated tightly with total expression but were not influenced by AD genetics. Lastly, we performed an initial characterization of these isoforms in transfected cells and found that, while full-length was expressed in a dispersed punctate fashion within the cytosol, isoforms lacking most or all of exon six tended to form extensive protein aggregates. In summary, expression is restricted to microglia, is increased with Alzheimer's neuropathology, and includes several isoforms that display a variable tendency to aggregate when expressed in vitro.