When Two Worlds Collide: The Contribution and Association Between Genetics (APOEε4) and Neuroinflammation (IL-1β) in Alzheimer’s Neuropathogenesis
<b>Introduction:</b> Here we consider the collision of a genetic factor and an essential instigator in Alzheimer’s neuropathogenesis: (i) the Alzheimer’s gene (APOEε4), which downregulates lysosomal autophagy and induces synthesis of (ii) the instigator, interleukin-1β (IL-1β), which dri...
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2025-08-01
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| author | Jagadeesh Narasimhappagari Ling Liu Meenakshisundaram Balasubramaniam Srinivas Ayyadevara W. Sue T. Griffin |
| author_facet | Jagadeesh Narasimhappagari Ling Liu Meenakshisundaram Balasubramaniam Srinivas Ayyadevara W. Sue T. Griffin |
| author_sort | Jagadeesh Narasimhappagari |
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| description | <b>Introduction:</b> Here we consider the collision of a genetic factor and an essential instigator in Alzheimer’s neuropathogenesis: (i) the Alzheimer’s gene (APOEε4), which downregulates lysosomal autophagy and induces synthesis of (ii) the instigator, interleukin-1β (IL-1β), which drives synthesis of βAPP for Aβ plaques and of MAPKp38 for phosphorylation of tau for formation of neurofibrillary tangles (NFTs), the two cardinal features of AD. <b>Methods:</b> RT-PCR, immunoblotting and immunohistochemistry techniques were used to assess the levels of IL-1β and its signaling cascade in ADε4,4, ε3,3, and age-matched controls (AMC3,3) in hippocampal regions of the brain. <b>Results:</b> IL-1β and its downstream signaling proteins TLR-2, MyD88, NFκB, COX-1, and COX-2 were greater in tissues from ADε4,4 than ADε3,3 or AMC3,3. Cathepsin B, D, and L levels, which play a pivotal role and are necessary for lysosomal autophagy, were lower in ADε4,4 than in ADε3,3 or AMC ε3,3. IL-1β and its downstream signaling cascade TLR-2, MyD88, NFκB, COX-1, and COX-2 expression levels were high in SH-SY5Y and T98G cells transfected with APOεE4. <b>Conclusions:</b> APOEε4 causes Alzheimer’s by downregulating autophagy, thus inducing IL-1β for Aβ plaque and neurofibrillary tangle formation. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-08-01 |
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| spelling | doaj-art-ec333da8492048d9bbcb104a29d0016e2025-08-20T04:00:55ZengMDPI AGCells2073-44092025-08-011415121610.3390/cells14151216When Two Worlds Collide: The Contribution and Association Between Genetics (APOEε4) and Neuroinflammation (IL-1β) in Alzheimer’s NeuropathogenesisJagadeesh Narasimhappagari0Ling Liu1Meenakshisundaram Balasubramaniam2Srinivas Ayyadevara3W. Sue T. Griffin4Donald W. Reynolds Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADonald W. Reynolds Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADonald W. Reynolds Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADonald W. Reynolds Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADonald W. Reynolds Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA<b>Introduction:</b> Here we consider the collision of a genetic factor and an essential instigator in Alzheimer’s neuropathogenesis: (i) the Alzheimer’s gene (APOEε4), which downregulates lysosomal autophagy and induces synthesis of (ii) the instigator, interleukin-1β (IL-1β), which drives synthesis of βAPP for Aβ plaques and of MAPKp38 for phosphorylation of tau for formation of neurofibrillary tangles (NFTs), the two cardinal features of AD. <b>Methods:</b> RT-PCR, immunoblotting and immunohistochemistry techniques were used to assess the levels of IL-1β and its signaling cascade in ADε4,4, ε3,3, and age-matched controls (AMC3,3) in hippocampal regions of the brain. <b>Results:</b> IL-1β and its downstream signaling proteins TLR-2, MyD88, NFκB, COX-1, and COX-2 were greater in tissues from ADε4,4 than ADε3,3 or AMC3,3. Cathepsin B, D, and L levels, which play a pivotal role and are necessary for lysosomal autophagy, were lower in ADε4,4 than in ADε3,3 or AMC ε3,3. IL-1β and its downstream signaling cascade TLR-2, MyD88, NFκB, COX-1, and COX-2 expression levels were high in SH-SY5Y and T98G cells transfected with APOεE4. <b>Conclusions:</b> APOEε4 causes Alzheimer’s by downregulating autophagy, thus inducing IL-1β for Aβ plaque and neurofibrillary tangle formation.https://www.mdpi.com/2073-4409/14/15/1216APOEε4Interleukin-1βNeuroinflammationautophagy |
| spellingShingle | Jagadeesh Narasimhappagari Ling Liu Meenakshisundaram Balasubramaniam Srinivas Ayyadevara W. Sue T. Griffin When Two Worlds Collide: The Contribution and Association Between Genetics (APOEε4) and Neuroinflammation (IL-1β) in Alzheimer’s Neuropathogenesis Cells APOEε4 Interleukin-1β Neuroinflammation autophagy |
| title | When Two Worlds Collide: The Contribution and Association Between Genetics (APOEε4) and Neuroinflammation (IL-1β) in Alzheimer’s Neuropathogenesis |
| title_full | When Two Worlds Collide: The Contribution and Association Between Genetics (APOEε4) and Neuroinflammation (IL-1β) in Alzheimer’s Neuropathogenesis |
| title_fullStr | When Two Worlds Collide: The Contribution and Association Between Genetics (APOEε4) and Neuroinflammation (IL-1β) in Alzheimer’s Neuropathogenesis |
| title_full_unstemmed | When Two Worlds Collide: The Contribution and Association Between Genetics (APOEε4) and Neuroinflammation (IL-1β) in Alzheimer’s Neuropathogenesis |
| title_short | When Two Worlds Collide: The Contribution and Association Between Genetics (APOEε4) and Neuroinflammation (IL-1β) in Alzheimer’s Neuropathogenesis |
| title_sort | when two worlds collide the contribution and association between genetics apoeε4 and neuroinflammation il 1β in alzheimer s neuropathogenesis |
| topic | APOEε4 Interleukin-1β Neuroinflammation autophagy |
| url | https://www.mdpi.com/2073-4409/14/15/1216 |
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