Neuroinflammation in Alzheimer Disease

Increasing evidence points to a pivotal role of immune processes in the pathogenesis of Alzheimer disease, which is the most prevalent neurodegenerative and dementia-causing disease of our time. Multiple lines of information provided by experimental, epidemiological, neuropathological and genetic studies suggest a pathological role for innate and adaptive immune activation in this disease. Here, we review the cell types and pathological mechanisms involved in disease development as well as the influence of genetics and lifestyle factors. Given the decade-long preclinical stage of Alzheimer disease, these mechanisms and their interactions are driving forces behind the spread and progression of the disease. The identification of treatment opportunities will require a precise understanding of the cells and mechanisms involved as well as a clear definition of their temporal and topographical nature. We will also discuss new therapeutic strategies for targeting neuroinflammation, which are now entering the clinic and showing promise for patients.

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References

Gotz J, Bodea L, Goedert M . Rodent models for Alzheimer disease. Nat Rev Neurosci. 2018; 19(10):583-598. DOI: 10.1038/s41583-018-0054-8. View

Sasaguri H, Hashimoto S, Watamura N, Sato K, Takamura R, Nagata K . Recent Advances in the Modeling of Alzheimer's Disease. Front Neurosci. 2022; 16:807473. PMC: 9009508. DOI: 10.3389/fnins.2022.807473. View

Sierksma A, Escott-Price V, De Strooper B . Translating genetic risk of Alzheimer's disease into mechanistic insight and drug targets. Science. 2020; 370(6512):61-66. DOI: 10.1126/science.abb8575. View

Eikelenboom P, STAM F . Immunoglobulins and complement factors in senile plaques. An immunoperoxidase study. Acta Neuropathol. 1982; 57(2-3):239-42. DOI: 10.1007/BF00685397. View

Griffin W, Sheng J, Roberts G, Mrak R . Interleukin-1 expression in different plaque types in Alzheimer's disease: significance in plaque evolution. J Neuropathol Exp Neurol. 1995; 54(2):276-81. DOI: 10.1097/00005072-199503000-00014. View

Lagomarsino V, Pearse 2nd R, Liu L, Hsieh Y, Fernandez M, Vinton E . Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors. Neuron. 2021; 109(21):3402-3420.e9. PMC: 8571042. DOI: 10.1016/j.neuron.2021.08.003. View

McGeer P, Itagaki S, TAGO H, McGeer E . Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett. 1987; 79(1-2):195-200. DOI: 10.1016/0304-3940(87)90696-3. View

Sheng J, Mrak R, Griffin W . Glial-neuronal interactions in Alzheimer disease: progressive association of IL-1alpha+ microglia and S100beta+ astrocytes with neurofibrillary tangle stages. J Neuropathol Exp Neurol. 1997; 56(3):285-90. View

McGeer P, Akiyama H, Itagaki S, McGeer E . Activation of the classical complement pathway in brain tissue of Alzheimer patients. Neurosci Lett. 1989; 107(1-3):341-6. DOI: 10.1016/0304-3940(89)90843-4. View

10.

Rogers J, Luber-Narod J, Styren S, CIVIN W . Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's disease. Neurobiol Aging. 1988; 9(4):339-49. DOI: 10.1016/s0197-4580(88)80079-4. View

11.

Styren S, CIVIN W, Rogers J . Molecular, cellular, and pathologic characterization of HLA-DR immunoreactivity in normal elderly and Alzheimer's disease brain. Exp Neurol. 1990; 110(1):93-104. DOI: 10.1016/0014-4886(90)90054-v. View

12.

Griffin W, Stanley L, Ling C, White L, MacLeod V, Perrot L . Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A. 1989; 86(19):7611-5. PMC: 298116. DOI: 10.1073/pnas.86.19.7611. View

13.

Heneka M, McManus R, Latz E . Inflammasome signalling in brain function and neurodegenerative disease. Nat Rev Neurosci. 2018; 19(10):610-621. DOI: 10.1038/s41583-018-0055-7. View

14.

Strauss S, Bauer J, Ganter U, Jonas U, Berger M, Volk B . Detection of interleukin-6 and alpha 2-macroglobulin immunoreactivity in cortex and hippocampus of Alzheimer's disease patients. Lab Invest. 1992; 66(2):223-30. View

15.

Moonen S, Koper M, Van Schoor E, Schaeverbeke J, Vandenberghe R, von Arnim C . Pyroptosis in Alzheimer's disease: cell type-specific activation in microglia, astrocytes and neurons. Acta Neuropathol. 2022; 145(2):175-195. DOI: 10.1007/s00401-022-02528-y. View

16.

Thal D, Arendt T, Waldmann G, Holzer M, Zedlick D, Rub U . Progression of neurofibrillary changes and PHF-tau in end-stage Alzheimer's disease is different from plaque and cortical microglial pathology. Neurobiol Aging. 1999; 19(6):517-25. DOI: 10.1016/s0197-4580(98)00090-6. View

17.

Boon B, Hoozemans J, Lopuhaa B, Eigenhuis K, Scheltens P, Kamphorst W . Neuroinflammation is increased in the parietal cortex of atypical Alzheimer's disease. J Neuroinflammation. 2018; 15(1):170. PMC: 5975447. DOI: 10.1186/s12974-018-1180-y. View

18.

Zotova E, Bharambe V, Cheaveau M, Morgan W, Holmes C, Harris S . Inflammatory components in human Alzheimer's disease and after active amyloid-β42 immunization. Brain. 2013; 136(Pt 9):2677-96. DOI: 10.1093/brain/awt210. View

19.

Franco-Bocanegra D, George B, Lau L, Holmes C, Nicoll J, Boche D . Microglial motility in Alzheimer's disease and after Aβ42 immunotherapy: a human post-mortem study. Acta Neuropathol Commun. 2019; 7(1):174. PMC: 6842157. DOI: 10.1186/s40478-019-0828-x. View

20.

Boche D, Nicoll J . Invited Review - Understanding cause and effect in Alzheimer's pathophysiology: Implications for clinical trials. Neuropathol Appl Neurobiol. 2020; 46(7):623-640. DOI: 10.1111/nan.12642. View