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It is also significantly increased with aging. Moreover, machine learning has identified it as a brain-derived protein most predictive of Alzheimer\u2019s disease (AD). HAPLN2 binds to CSPGs that may sequester aggregation-prone proteins and also restrict neuronal plasticity. Because the apolipoprotein 4 (APOE4) allele increases AD risk, in the present study we have examined hippocampal lysates from APOE3 and APOE4 targeted replacement (TR) mice using unbiased proteomics, Western blot and hippocampal immunostaining. With proteomics, we observe 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, and 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), which accumulates in cerebral blood vessels harboring amyloid, in APOE4 mice. In Western blot studies, lysates from APOE4 mice also showed significantly reduced levels chondroitin-6 sulfated proteoglycans, which makes PNNs more susceptible to proteolysis and less inhibitory. In addition, immunostaining studies 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, and suggest that future studies should assess PNNs, peri-nodal structure and axonal conduction in the background of APOE4.<\/jats:p>","DOI":"10.1101\/2025.11.09.687435","type":"posted-content","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T03:55:19Z","timestamp":1762833319000},"source":"Crossref","is-referenced-by-count":1,"title":["Increased levels of HAPLN2, which anchors dense extracellular matrix, in the hippocampus of APOE4 targeted replacement mice"],"prefix":"10.64898","author":[{"given":"Samantha","family":"Deasy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Amontree","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"Colon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Thorland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kush","family":"Modi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2739-3724","authenticated-orcid":false,"given":"Katie","family":"Hummel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismary","family":"Blanco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Griffin","family":"Greco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Maguire-Zeiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Conant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025111215200916000_2025.11.09.687435v1.1","doi-asserted-by":"crossref","first-page":"106057","DOI":"10.1016\/j.nbd.2023.106057","article-title":"CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice","volume":"179","year":"2023","journal-title":"Neurobiol Dis"},{"key":"2025111215200916000_2025.11.09.687435v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.05.017"},{"key":"2025111215200916000_2025.11.09.687435v1.3","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciy807"},{"key":"2025111215200916000_2025.11.09.687435v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/J.NEUROBIOLAGING.2023.05.012"},{"key":"2025111215200916000_2025.11.09.687435v1.5","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23974"},{"key":"2025111215200916000_2025.11.09.687435v1.6","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.14887"},{"key":"2025111215200916000_2025.11.09.687435v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2014.11.013"},{"key":"2025111215200916000_2025.11.09.687435v1.8","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2387-19.2020"},{"key":"2025111215200916000_2025.11.09.687435v1.9","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6267-11.2013"},{"key":"2025111215200916000_2025.11.09.687435v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/416636a"},{"key":"2025111215200916000_2025.11.09.687435v1.11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1300454110"},{"key":"2025111215200916000_2025.11.09.687435v1.12","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2010.06647.x"},{"issue":"9","key":"2025111215200916000_2025.11.09.687435v1.13","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1093\/jnen\/nlw062","article-title":"Tenascin-C Is Associated with Cored Amyloid-beta Plaques in Alzheimer Disease and Pathology Burdened Cognitively Normal Elderly","volume":"75","year":"2016","journal-title":"J Neuropathol Exp Neurol"},{"key":"2025111215200916000_2025.11.09.687435v1.14","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-8-115"},{"key":"2025111215200916000_2025.11.09.687435v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.10.056"},{"key":"2025111215200916000_2025.11.09.687435v1.16","doi-asserted-by":"crossref","first-page":"782399","DOI":"10.3389\/fnsys.2021.782399","article-title":"Gamma Oscillations in Alzheimer\u2019s Disease and Their Potential Therapeutic Role","volume":"15","year":"2021","journal-title":"Front Syst Neurosci"},{"key":"2025111215200916000_2025.11.09.687435v1.17","doi-asserted-by":"crossref","unstructured":"Murty, D.V. , et al., Stimulus-induced gamma rhythms are weaker in human elderly with mild cognitive impairment and Alzheimer\u2019s disease. 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