Alzheimer’s Neuropathology: Neuroinflammation in Patients Exemplifies the Presence of Both a Neuronal and Immunological Response

Increasing evidence suggests that Alzheimer’s disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterized by release of inflammatory mediators, which contribute to disease progression and severity [1]. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer’s disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression [2]. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer’s disease.

Emerging evidence suggests that inflammation has a causal role in disease pathogenesis, and understanding and control of interactions between the immune system and the nervous system might be key to the prevention or delay of most late-onset central nervous system diseases (CNS). In Alzheimer’s disease, neuroinflammation is not a system activated by senile plaques and neurofibrillar tangles, but instead contributes as much to pathogenesis as do plaques and tangles themselves. The important role of neuroinflammation is supported by findings that genes for immune receptors, including TREM2 and CD33/34 are associated with Alzheimer’s disease [3]. 

A specific aspect of the immune system that is under investigation  are the resident macrophage cells of the CNS, known as microglia. Macrophages, or microglia in the CNS, are phagocytic immune cells that can destroy immune system targeted cells. Microglia constantly survey their assigned brain regions for the presence of pathogens and cellular debris and simultaneously provide factors that support tissue maintenance [4]. At the same time, microglia are important players in the maintenance and plasticity of neuronal circuits, contributing to the protection and remodelling of synapses. Once activated by pathological triggers, such as neuronal death or protein aggregates, microglia extend their processes to the site of injury, and migrate to the lesion, where they initiate an innate immune response. Detection of pathological triggers is mediated by receptors that recognise danger-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) [5]. In Alzheimer’s disease, microglia are able to bind to soluble amyloid β (Aβ) oligomers and Aβ fibrils via cell-surface receptors (SCARA1, CD36, CD14, α6β1 integrin, CD47), and Toll-like receptors (TLR2, TLR4, TLR6, and TLR9), and this process is thought to be part of the inflammatory reaction in Alzheimer’s disease [6]. The Aβ peptide is derived from amyloid precursor protein (APP) by sequential cleavages by two membrane-bound proteases. The 42-amino acid form of Aβ has a particularly strong tendency to form soluble oligomers and fibrils [7]. Binding of Aβ with CD36, TLR4, and TLR6 results in activation of microglia, which start to produce proinflammatory cytokines and chemokines. These cytokines and chemokines act to recruit other immune cells to the site of injury [8]. 

In response to receptor ligation, microglia start to engulf Aβ fibrils by phagocytosis. As a result, these fibrils enter the endolysosomal pathway (when the fibrils are exocytosed, they pass through an endosome that targets the fibrils to the lysosome) [6]. By contrast with fibrillar Aβ, which is mostly resistant to enzymatic degradation, soluble Aβ can be degraded by various extracellular proteases. In cases of Alzheimer’s disease, ineffective clearance of Aβ has been identified as a major pathogenic pathway. Increased cytokine concentrations, by the downregulation (lessened transcription of the gene responsible) of Aβ phagocytosis receptors, are suggested to be responsible for insufficient microglial phagocytic capacity [9]. Further support for the hypothesis of compromised microglial function is provided by two studies identifying rare mutations that convey an increased risk of Alzheimer’s disease. A rare mutation in the extracellular domain of TREM2 increases risk of Alzheimer’s disease. TREM2 is highly expressed by microglia, and mediates phagocytic clearance of neuronal debris (including the fibril aggregates) [10]. Although a TREM2 ligand (the binding molecule) has not yet been discovered, TREM2 binding activity is detected on reactive astrocytes (neuronal support cells that help maintain brain homeostasis) surrounding amyloid plaques and on damaged neurons and oligodendrocytes (other neuronal support cells). Likewise, a single-nucleotide polymorphism (SNP) in the gene encoding the microglial surface receptor CD33 reduces Aβ phagocytosis by peripheral macrophages [11]. 

The emerging role of microglia activation in Alzheimer’s disease pathogenesis makes these cells a legitimate therapeutic target. However, depending on the circumstances, microglia activation can have both beneficial and detrimental effects. Thus, microglia might have different roles and effects depending on the particular disease stage and which brain region is affected [12]. After exposure to a DAMP or PAMP, the acute microglial reaction aims to remove the recognised abnormality or pathological change. In the case of Alzheimer’s disease, this type of inflammatory reaction is sterile because it involves the same receptors but no living pathogens. Under normal circumstances, such a reaction quickly resolves pathological changes with immediate benefit to the nearby environment [13]. However, in Alzheimer’s disease, several mechanisms, including ongoing formation of Aβ aggregates and positive-feedback loops between inflammation and APP processing (cytokines released during inflammation, increases the formation of Aβ aggregates), compromise cessation of inflammation [14]. Instead, further accumulation of Aβ, neuronal debris, and, most probably, further activating factors establish chronic, non-resolving inflammation [4]. Sustained exposure to Aβ, chemokines, cytokines, and other inflammatory mediators seems to be responsible for the persistent functional impairment of microglial cells seen at plaque sites [8].

Furthermore, evidence exists that neuroinflammation might drive the pathogenic process in Alzheimer’s disease. The brain can no longer be viewed as an immune-privileged organ, and advances in immunology need to be integrated into the known pathogenic pathways of diverse neurodegenerative disorders [15]. The ligand–receptor interactions in the CNS microenvironment that keep microglia under tight control in the healthy brain are perturbed in chronic neurodegenerative disease, but when and how this occurs in Alzheimer’s disease is unclear. Although the simple idea of activated microglia has been a useful one, it has no doubt hindered understanding and recognition of the diversity of microglial phenotypes and the extraordinary plasticity of these cells [16]. An important goal of future studies will be to better understand the individual contributions of microglia and other cell types to the neuroinflammatory response during the course of Alzheimer’s disease.

The innate immune cells of the brain respond rapidly to systemic events, and these responses are exaggerated in the ageing and diseased brain. In future studies, the effect of systemic comorbidities of Alzheimer’s disease (such as diabetes and hypertension), associated systemic inflammation, and ageing as a major risk factor for Alzheimer’s disease, should be considered in efforts to understand and exploit the immunological processes associated with the disease [2]. Recognition that modification of the immune system contributes to pathogenesis of chronic neurodegenerative diseases opens many potential routes to delay their onset and progression.

References 

1. McGeer, P. L., & McGeer, E. G. (1995). The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain research. Brain research reviews, 21(2), 195–218. https://doi.org/10.1016/0165-0173(95)00011-9\
2. Eikelenboom, P., Veerhuis, R., Scheper, W., Rozemuller, A. J., van Gool, W. A., & Hoozemans, J. J. (2006). The significance of neuroinflammation in understanding Alzheimer’s disease. Journal of neural transmission (Vienna, Austria : 1996), 113(11), 1685–1695. https://doi.org/10.1007/s00702-006-0575-6
3. Zhao, Y., Wu, X., Li, X., Jiang, L. L., Gui, X., Liu, Y., Sun, Y., Zhu, B., Piña-Crespo, J. C., Zhang, M., Zhang, N., Chen, X., Bu, G., An, Z., Huang, T. Y., & Xu, H. (2018). TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function. Neuron, 97(5), 1023–1031.e7. https://doi.org/10.1016/j.neuron.2018.01.031
4. Patel, N. S., Paris, D., Mathura, V., Quadros, A. N., Crawford, F. C., & Mullan, M. J. (2005). Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer’s disease. Journal of neuroinflammation, 2(1), 9. https://doi.org/10.1186/1742-2094-2-9
5. Smith, J. A., Das, A., Ray, S. K., & Banik, N. L. (2012). Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain research bulletin, 87(1), 10–20. https://doi.org/10.1016/j.brainresbull.2011.10.004
6. Liu, S., Liu, Y., Hao, W., Wolf, L., Kiliaan, A. J., Penke, B., Rübe, C. E., Walter, J., Heneka, M. T., Hartmann, T., Menger, M. D., & Fassbender, K. (2012). TLR2 is a primary receptor for Alzheimer’s amyloid β peptide to trigger neuroinflammatory activation. Journal of immunology (Baltimore, Md. : 1950), 188(3), 1098–1107. https://doi.org/10.4049/jimmunol.1101121
7. Bronzuoli, M. R., Iacomino, A., Steardo, L., & Scuderi, C. (2016). Targeting neuroinflammation in Alzheimer’s disease. Journal of inflammation research, 9, 199–208. https://doi.org/10.2147/JIR.S86958
8. Murphy, M. P., & LeVine, H., 3rd (2010). Alzheimer’s disease and the amyloid-beta peptide. Journal of Alzheimer’s disease : JAD, 19(1), 311–323. https://doi.org/10.3233/JAD-2010-1221
9. Zhang, Yw., Thompson, R., Zhang, H. et al. APP processing in Alzheimer’s disease. Mol Brain 4, 3 (2011). https://doi.org/10.1186/1756-6606-4-3
10. Sastre, M., Walter, J., & Gentleman, S. M. (2008). Interactions between APP secretases and inflammatory mediators. Journal of neuroinflammation, 5, 25. https://doi.org/10.1186/1742-2094-5-25
11. Heneka, M. T., Carson, M. J., El Khoury, J., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., Herrup, K., Frautschy, S. A., Finsen, B., Brown, G. C., Verkhratsky, A., Yamanaka, K., Koistinaho, J., Latz, E., Halle, A., Petzold, G. C., … Kummer, M. P. (2015). Neuroinflammation in Alzheimer’s disease. The Lancet. Neurology, 14(4), 388–405. https://doi.org/10.1016/S1474-4422(15)70016-5
12. Matsui, T., Ingelsson, M., Fukumoto, H., Ramasamy, K., Kowa, H., Frosch, M. P., Irizarry, M. C., & Hyman, B. T. (2007). Expression of APP pathway mRNAs and proteins in Alzheimer’s disease. Brain research, 1161, 116–123. https://doi.org/10.1016/j.brainres.2007.05.050
13. Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C., & Gage, F. H. (2010). Mechanisms underlying inflammation in neurodegeneration. Cell, 140(6), 918–934. https://doi.org/10.1016/j.cell.2010.02.016
14. Verbeeck, C., Carrano, A., Chakrabarty, P., Jankowsky, J. L., & Das, P. (2017). Combination of Aβ Suppression and Innate Immune Activation in the Brain Significantly Attenuates Amyloid Plaque Deposition. The American journal of pathology, 187(12), 2886–2894. https://doi.org/10.1016/j.ajpath.2017.08.010
15. De Strooper, B., & Karran, E. (2016). The Cellular Phase of Alzheimer’s Disease. Cell, 164(4), 603–615. https://doi.org/10.1016/j.cell.2015.12.056
16. Petrovitch, H., White, L. R., Izmirilian, G., Ross, G. W., Havlik, R. J., Markesbery, W., Nelson, J., Davis, D. G., Hardman, J., Foley, D. J., & Launer, L. J. (2000). Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia aging Study. Neurobiology of aging, 21(1), 57–62. https://doi.org/10.1016/s0197-4580(00)00106-8