Christine Abreo

Background: Alzheimer’s disease (AD) is a complex progressive neurodegenerative disorder acquired mid to late life that presents as cortical atrophy from neuroinflammation and neurodegeneration¹. AD causes cognitive impairment, difficulty with familiar tasks, and impaired judgment. Additionally, there is no explicit causative agent, diagnostic test, nor treatment for AD, presenting a wide scientific gap¹. Upon post mortem study, AD is characterized by presence of amyloid B plaques which have been hypothesized to contribute to neuroinflammation². Traumatic brain injuries (TBI) on the other hand have a wide range of both severity and cause, all of which lead to neuroinflammation. A post mortem study showed that ½ of TBI had increased amyloid plaques³. The lipoprotein ApoE is the strongest genetic risk factor for AD as it facilitates amyloid-β plaque in the brain. ApoE can be present as varying genotypic combinations involving isoforms ApoE2, E3, and E4⁴. ApoE plays isoform-dependent roles in injury-induced neurogenesis following TBI suggesting a genotype specific approach to AD and amyloid-β treatment⁵.

Objective: This review investigated ApoE isotype specific responses to attempted treatments for Alzheimer’s Disease with an emphasis on TBI prognosis.

Search Methods: A search for primary articles between years 2019 – 2024 was conducted using the PubMed database. Key search terms were: “Alzheimer’s Disease ApoE,” “traumatic brain injury,” and “ApoE isoforms.”

Results: A study conducted at UC Davis was conducted to explore the role of ApoE in hippocampal injury-induced neurogenesis using a controlled cortical impact injury model on mice⁵. Post mortem ApoE-/- mice showed less complexity and a decreased length of dendritic trees for both controlled and pathological conditions indicating decreased neuronal connectivity⁵. The impairments in length and dendrite complexity were not present in newborn neurons as labeled by an eGFP-expressing retrovirus⁵. Injured and non-injured ApoE-/- mice had significant decreases in spine density as well as impaired spatial learning and memory suggesting complete ApoE knockout inefficiency⁵. A different study also using induced ApoE deficient mice found that ApoE-/-;APPPS1 genotypes led to reduced plaque compaction, microglial clustering reduction, and increased dystrophic neurites around plaques⁶. The third and most applicable study involved ApoE3 and ApoE4 isoform induced mice under a lateral fluid percussion model and a Bryostatin-1 treatment⁷. Bryostatin-1, a natural lactone derived from marine bryozoan, is a PKCe activator that has been shown to subsequently increase brain derived neurotrophic factor levels which support neurogenesis and differentiation⁷. Due to ApoE4 carriers having increased genetic predisposition to amyloid-β levels and reduced serum BDNF levels, it was hypothesized that bryostatin-1 would counteract this and reflect similar cognitive benefits following injury⁷. Treated mice displayed reduced levels of TNF-α and neurodegeneration as well as increased cognitive, motor, spatial and learning memory scores that were comparable to those of ApoE3 mice⁷.

Conclusions: Studies have demonstrated that ApoE complete knockout in animal models is ineffective which suggests focusing on treatments for amyloid-β pathology that take advantage of the genetic ApoE predisposition. The promising effects of Bryostatin-1 may be beneficial for altering TBI-induced neurodegeneration and reduce progression to AD.

Works Cited:

1. Centers for Disease Control and Prevention. Alzheimer’s Disease and Related Dementias. CDC. Published October 26, 2020. https://www.cdc.gov/aging/aginginfo/alzheimers.htm
2. Knopman DS, Amieva H, Petersen RC, et al. Alzheimer disease. Nature Reviews Disease Primers. 2021;7(1). doi:https://doi.org/10.1038/s41572-021-00269-y
3. Mohamed AZ, Cumming P, Srour H, et al. Amyloid pathology fingerprint differentiates post-traumatic stress disorder and traumatic brain injury [published correction appears in Neuroimage Clin. 2019;22:101829]. Neuroimage Clin. 2018;19:716-726. Published 2018 Jun 5. doi:10.1016/j.nicl.2018.05.016
4. Mahan TE, Wang C, Bao X, Choudhury A, Ulrich JD, Holtzman DM. Selective reduction of astrocyte apoE3 and apoE4 strongly reduces Aβ accumulation and plaque-related pathology in a mouse model of amyloidosis. Mol Neurodegener. 2022;17(1):13. Published 2022 Feb 2. doi:10.1186/s13024-022-00516-0
5. Yu TS, Tensaouti Y, Stephanz EP, et al. Astrocytic ApoE underlies maturation of hippocampal neurons and cognitive recovery after traumatic brain injury in mice. Commun Biol. 2021;4(1):1303. Published 2021 Nov 18. doi:10.1038/s42003-021-02841-4
6. Ulrich JD, Ulland TK, Mahan TE, et al. ApoE facilitates the microglial response to amyloid plaque pathology. J Exp Med. 2018;215(4):1047-1058. doi:10.1084/jem.20171265
7. Giarratana AO, Zheng C, Reddi S, et al. APOE4 genetic polymorphism results in impaired recovery in a repeated mild traumatic brain injury model and treatment with Bryostatin-1 improves outcomes. Sci Rep. 2020;10(1):19919. Published 2020 Nov 16. doi:10.1038/s41598-020-76849-x