Interplay between innate immunity and alzheimer disease: apoe and trem2 in the spotlight

ABSTRACT Alzheimer disease is more than a pure proteopathy. Chronic neuroinflammation stands out during the pathogenesis of the disease and in turn modulates disease progression. The central

nervous system (CNS) is separated from the blood circulation by the blood–brain barrier. In Alzheimer disease, neuroinflammation heavily relies on innate immune responses that are primarily

mediated by CNS-resident microglia. _APOE_ (which encodes apolipoprotein E) is the strongest genetic risk factor for Alzheimer disease, and APOE was recently shown to affect the disease in

part through its immunomodulatory function. This function of APOE is likely linked to triggering receptor expressed on myeloid cells 2 (TREM2), which is expressed by microglia in the CNS.

Here, we review the rapidly growing literature on the role of disease-associated microglia, TREM2 and APOE in the pathogenesis of Alzheimer disease and present an integrated view of innate

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support SIMILAR CONTENT BEING VIEWED BY OTHERS NEUROINFLAMMATION IN ALZHEIMER DISEASE Article 09 December 2024 IMMUNE MECHANISMS AND SHARED IMMUNE TARGETS IN NEURODEGENERATIVE DISEASES

Article 16 December 2024 MONOCYTE-DERIVED MACROPHAGES ACT AS REINFORCEMENTS WHEN MICROGLIA FALL SHORT IN ALZHEIMER’S DISEASE Article 06 January 2025 REFERENCES * Alzheimer, A. Über eine

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murine M1 and M2 macrophages. _PLOS ONE_ 10, e0145342 (2015). PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS This work was funded by US National Institutes of

Health grants R01AG047644, R01NS090934 and R01NS034467 and support from the JPB Foundation, the Tau Consortium and the Cure Alzheimer Disease Fund to D.M.H. REVIEWER INFORMATION _Nature

Reviews Immunology_ thanks O. Butovsky and M. Heneka for their assistance with the peer review of this manuscript. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Neurology, Hope

Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA Yang Shi & David M.

Holtzman Authors * Yang Shi View author publications You can also search for this author inPubMed Google Scholar * David M. Holtzman View author publications You can also search for this

author inPubMed Google Scholar CONTRIBUTIONS Y.S. wrote the draft of the manuscript. D.M.H. reviewed and edited the manuscript. CORRESPONDING AUTHOR Correspondence to David M. Holtzman.

ETHICS DECLARATIONS COMPETING INTERESTS D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics. D.M.H. is on the scientific advisory board of Denali, Genentech and

Proclara. D.M.H. consults for AbbVie and Eli Lilly. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and

institutional affiliations. GLOSSARY * Amyloid-β A small peptide that is a major component of amyloid deposits in the brain and cerebrovasculature. It is generated from cleavage of amyloid

precursor protein (APP). Depending on the carboxy-terminal cleavage site, amyloid-β peptides of varying lengths (36–43 amino acids; denoted as Aβ36–Aβ43) can be generated, among which Aβ40

and Aβ42 are the most prevalent species. * Tau A microtubule-binding protein synthesized primarily in neurons. Under normal conditions, tau is most abundantly located in axons and serves to

stabilize microtubules. In Alzheimer disease, tau becomes hyperphosphorylated, dissociates from microtubules, translocates from axons to neuronal cell bodies and dendrites and

self-aggregates to form neurofibrillary tangles. * Aβ42/Aβ40 ratio Aβ42 is more fibrillogenic than Aβ40. The level of Aβ42 produced relative to Aβ40 determines the propensity of amyloid

plaque formation. * Kainic acid A potent neuroexcitatory amino acid that serves as an agonist for kainate-class ionotropic glutamate receptors. High doses of kainic acid induce neuronal

death by overexcitation of neurons. * 5XFAD mice An amyloid-β-depositing mouse model that overexpresses mutant human amyloid precursor protein (APP) carrying the Swedish (K670N and M671L),

Florida (I716V) and London (V717I) mutations linked to familial Alzheimer disease along with human presenilin 1 (PS1) carrying the M146L and L286V mutations. Both transgenes are controlled

under the _Thy1_ promoter. These mice accumulate high levels of intraneuronal Aβ42 around 6 weeks of age, followed by plaque deposition around 2 months of age. * APPSwePSEN1dE9 mice An

amyloid-β-depositing mouse model that expresses a chimeric mouse–human _APP_ transgene carrying the Swedish mutations (K670N and M671L) and a mutant _PSEN1_ transgene lacking exon 9 (dE9)

under the prion promoter. These mice begin to develop amyloid-β pathology around 6 months of age. * Ionized calcium-binding adaptor molecule 1 (IBA1). A microglia marker protein in the

central nervous system that binds calcium and actin. It is involved in RAC GTPase-dependent membrane ruffling and phagocytosis during microglial cell activation. * 3xTg-AD mice A mouse model

that harbours three mutant human genes (_APP_ K670N,M671L, _PSEN1_M146V and _MAPT_ P301L) and sequentially develops amyloid-β pathology and tau pathology starting at 6 months of age. * htau

mice A mouse model that expresses all six human tau isoforms, including 3R and 4R tau, under the endogenous human _MAPT_ promoter and expresses no murine tau. These mice start to develop

tau pathology around 9 months of age. * rTg4510 mice A tauopathy mouse model overexpressing the 0N4R human tau isoform carrying the P301L mutation linked to familial frontotemporal dementia.

Tau transgene expression is largely restricted to the forebrain by the _Camk2a_ promoter and is regulatable by doxycycline. These mice develop tau pathology around 3–4 months of age and

show substantial neuronal loss by 6 months of age. * P301S mice A tauopathy mouse model overexpressing the 1N4R human tau isoform carrying the P301S mutation found in patients with

frontotemporal dementia. These mice begin to accumulate tau pathology at 4–5 months of age and develop severe brain atrophy at 9 months of age. * APOE-targeted replacement mice (APOE-TR

mice). These mice express human apolipoprotein E (APOE) in place of the murine APOE under the endogenous murine _Apoe_ promoter. Therefore, the expression level and pattern of human APOE are

maintained in a physiological form. * APPPS1-21 mice An amyloid-β-depositing mouse model that harbours mutant human transgenes of _APP_ (K670N and M671L) and _PSEN1_ (L166P), which are both

under the control of the _Thy1_ promoter. These mice begin to develop amyloid plaques in the neocortex at approximately 6 weeks of age, followed by deposits in the hippocampus at 3–4 months

of age. * Superoxide dismutase 1 mice (SOD1 mice). A mouse model for amyotrophic lateral sclerosis (ALS) that overexpresses human SOD1 carrying the G93A mutation. These mice recapitulate

phenotypes in human patients with ALS, showing motor neuron loss in the spinal cord and paralysis in one or more limbs. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE

CITE THIS ARTICLE Shi, Y., Holtzman, D.M. Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. _Nat Rev Immunol_ 18, 759–772 (2018).

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