Authors
Deasy, S., Amontree, M., Colon, Z. A., Thorland, E., Modi, K., Hummel, K. A., Blanco, I., Greco, G. A., Maguire-Zeiss, K., Conant, K.
Abstract
Hyaluronan and proteoglycan link protein 2 (HAPLN2) / Brain link protein-1 (Bral1) is important for the binding of chondroitin sulfate proteoglycans (CSPGs) to hyaluronan and thus for the formation of specific types of brain extracellular matrix (ECM). It is also significantly increased with aging. Machine learning has also identified it as a brain-derived protein most predictive of Alzheimers disease (AD). HAPLN2 binds to CSPGs that may sequester aggregation-prone proteins and also restrict neuronal plasticity. Apolipoprotein 4 (APOE4) allele increases AD risk and thus in the present study we have examined hippocampal lysates from APOE3 and APOE4 targeted replacement (TR) mice using unbiased proteomics as well as Western blot and hippocampal immunostaining. Proteomics data show that HAPLN2 is among the most significantly upregulated proteins in APOE4 mice. Prior work suggests HAPLN2 is particularly important to the assembly of perinodal matrix. Herein we show that it also co-localizes with Wisteria floribunda agglutinin (WFA) positive perineuronal nets (PNNs). PNNs represent a dense form of ECM that can increase GABAergic neurotransmission to alter overall excitatory/inhibitory (E/I) balance and neuronal oscillations important to mood and memory. Proteomics also detected elevated levels of high temperature requirement peptidase-1 (HTRA1). HTRA1 accumulates in cerebral blood vessels harboring amyloid in APOE4 mice. Western blot studies of lysates from APOE4 mice also showed significantly reduced levels chondroitin-6 sulfated proteoglycans. This change makes PNNs more susceptible to proteolysis and less inhibitory. Immunostaining studies further showed that levels of the PNN component aggrecan were increased in the hippocampus of APOE4 animals. Overall these findings contribute to an emerging body of literature suggesting that brain extracellular matrix may be altered with aging and other risk factors for AD. Findings also suggest that future studies should assess peri-nodal structure and axonal conduction in the background of APOE4.
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bioRxiv
The authors list and abstract were imported from bioRxiv on 12 Nov 2025.
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