Anti-inflammatory and Immune Therapy for Alzheimers Disease: Current Status and Future Directions

Walker, Douglas; Lue, Lih-Fen

doi:10.2174/157015907782793667

Cited by 66Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Anti-inflammatory and Immune Therapy for Alzheimers Disease: Current Status and Future Directions

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Walker, Douglas, Lue, Lih-Fen·2007·Current Neuropharmacology

DOI 10.2174/157015907782793667PMC PMC2644496

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Abstract

From the initial characterizations of inflammatory responses in Alzheimer's disease (AD) affected brains, namely the demonstration of activated microglia and reactive astrocytes, complement system activation, increased production of proinflammatory cytokines, and evidence for microglial-produced neurotoxins, there was hope that reducing inflammation might be a feasible treatment for this memory-robbing disease. This hope was supported by a number of epidemiology studies demonstrating that patients who took non-steroidal anti-inflammatory drugs had significantly lower risk of developing AD. However, clinical trials of anti-inflammatories have not shown effectiveness, and in recent years, the concept of immune therapy has become a treatment option as animal studies and clinical trials with Abeta vaccines have demonstrated enhanced amyloid removal through stimulation of microglial phagocytosis.This review will examine the current status of whether inhibiting inflammation is a valid therapeutic target for treating AD; what lessons have come from the clinical trials; what new pathways and classes of agents are being considered; and how this field of research can progress towards new therapeutics. We will examine a number of agents that have shown effectiveness in reducing inflammation amongst other demonstrated mechanisms of action. The major focus of much AD drug discovery has been in identifying agents that have anti-amyloid properties; however, a number of these agents were first identified for their anti-inflammatory properties. As drug development and clinical testing is a costly and lengthy endeavor, sound justification of new therapeutic targets is required. Possible future directions for AD anti-inflammatory or immune clearance therapy will be discussed based on recent experimental data.

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Past clinical trials with various NSAIDs and glucocorticoids failed to rescue cognitive deficits in AD patients or prevent disease progression despite promising data from preclinical animal studies.
“In the past, clinical trials with various NSAIDs and glucocortoroids failed to rescue cognitive deficits in AD patients or prevent disease progression despite promising data from preclinical animal studies [186].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [186]
Phytochemicals' activity against Alzheimer's disease occurs through anti-amyloid, anticholinesterase, anti-inflammatory, and antioxidant mechanisms.
“Phytochemicals’ activity against AD occurred through different mechanisms such as their anti-amyloid, anticholinesterase, anti-inflammatory, and antioxidant properties [198].”
From Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation (2022) · cites this paper as [198]

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Both the d -(+) and l -(−) Enantiomers of Nicotine Inhibit Aβ Aggregation and Cytotoxicity
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Neuropathological Analysis of Dementia in a Japanese Leprosarium
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Glial contributions to neurodegeneration in tauopathies
Leyns, C. E. G., & Holtzman, D. M. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0192-x · Cited by 409 · see citing works
Urolithin A attenuates memory impairment and neuroinflammation in APP/PS1 mice
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Naturally derived anti-inflammatory compounds from Chinese medicinal plants
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Microglia Activation and Anti-inflammatory Regulation in Alzheimer’s Disease
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Alzheimer's disease: the pros and cons of pharmaceutical, nutritional, botanical, and stimulatory therapies, with a discussion of treatment strategies from the perspective of patients and practitioners.
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Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation
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Key role of MIF-related neuroinflammation in neurodegeneration and cognitive impairment in Alzheimer’s disease
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Huperzine a improves chronic inflammation and cognitive decline in rats with cerebral hypoperfusion
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Reelin-mediated signaling in neuropsychiatric and neurodegenerative diseases
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Bioinformatics methods in drug repurposing for Alzheimer’s disease
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Inhibition of c-Jun kinase provides neuroprotection in a model of Alzheimer's disease
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Protective effect of antirheumatic drugs on dementia in rheumatoid arthritis patients
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Initiative, A. D. N., Bonham, L. W., Desikan, R. S., & Yokoyama, J. S. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0339-y · Cited by 70 · see citing works
The Role of the Microbiota-Gut-Brain Axis in the Development of Alzheimer’s Disease
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Antarctic Krill Oil Diet Protects against Lipopolysaccharide-Induced Oxidative Stress, Neuroinflammation and Cognitive Impairment
Choi, J. Y., Jang, J., Son, D., Im, H.-S., Kim, J. E., Park, J. H., Choi, W., Han, S., & Hong, J. T. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122554 · Cited by 57 · see citing works
Nanoparticle formulations that allow for sustained delivery and brain targeting of the neuropeptide oxytocin
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Prefilament tau species as potential targets for immunotherapy for Alzheimer disease and related disorders
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Central nervous system delivery of large molecules: challenges and new frontiers for intrathecally administered therapeutics
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Obovatol improves cognitive functions in animal models for Alzheimer’s disease
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Naringin Dihydrochalcone Ameliorates Cognitive Deficits and Neuropathology in APP/PS1 Transgenic Mice
Yang, W., Zhou, K., Zhou, Y., An, Y., Hu, T., Lu, J. N., Huang, S., & Pei, G. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00169 · Cited by 46 · see citing works
The Potential Role of Herpes Simplex Virus Type 1 and Neuroinflammation in the Pathogenesis of Alzheimer's Disease
Laval, K., & Enquist, L. W. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.658695 · Cited by 40 · see citing works
Clinical Applications of Small-molecule PET Radiotracers: Current Progress and Future Outlook
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Urolithin A exhibits a neuroprotective effect against Alzheimer’s disease by inhibiting DYRK1A activity
Tu, H., SU, C., Peng, C.-S., Lin, T. E., Fu, W.-C. H., Hsu, K., Hwang, T., & Pan, S. (2023) · Journal of Food and Drug Analysis · doi:10.38212/2224-6614.3462 · Cited by 35 · see citing works
Alleviation of Cognitive Impairment-like Behaviors, Neuroinflammation, Colitis, and Gut Dysbiosis in 5xFAD Transgenic and Aged Mice by Lactobacillus mucosae and Bifidobacterium longum
Ma, X., Kim, J.-K., Shin, Y.-J., Son, Y.-H., Lee, D.-Y., Park, H.-S., & Kim, D. (2023) · Nutrients · doi:10.3390/nu15153381 · Cited by 34 · see citing works
Immunology meets neuroscience – Opportunities for immune intervention in neurodegenerative diseases
Lynch, M. A., & Mills, K. H. G. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2011.05.013 · Cited by 33 · see citing works
Dual impact of neuroinflammation on cognitive and motor impairments in Alzheimer's disease
Fakorede, S., Lateef, O. M., Garuba, W. A., Akosile, P. O., Okon, D. A., & Aborode, A. T. (2025) · Journal of Alzheimer s Disease Reports · doi:10.1177/25424823251341870 · Cited by 33 · see citing works
Systems Pharmacological Approach to Investigate the Mechanism ofAcori Tatarinowii Rhizomafor Alzheimer’s Disease
Song, Z., Yin, F., Xiang, B., Lan, B., & Cheng, S. (2018) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2018/5194016 · Cited by 31 · see citing works
Rapamycin inhibits lipopolysaccharide-induced neuroinflammation in vitro and in vivo
Mengke, N.-S., Hu, B., Han, Q., Deng, Y., Fang, M., Xie, D., Li, A., & Zeng, H. (2016) · Molecular Medicine Reports · doi:10.3892/mmr.2016.5883 · Cited by 30 · see citing works
Control of neuroinflammation as a therapeutic strategy for amyotrophic lateral sclerosis and other neurodegenerative disorders
Mosley, R. L., & Gendelman, H. E. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2009.12.018 · Cited by 29 · see citing works
Asiaticoside Mitigates Alzheimer’s Disease Pathology by Attenuating Inflammation and Enhancing Synaptic Function
Liu, S., Chen, L., Li, J., Sun, Y., Xu, Y., Li, Z., Zhu, Z., & Li, X. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241511976 · Cited by 28 · see citing works
Elevation of inactive cleaved annexin A1 in the neocortex is associated with amyloid, inflammatory and apoptotic markers in neurodegenerative dementias
Chua, X. Y., Chong, J. R., Cheng, A. L., Lee, J. H., Ballard, C. G., Aarsland, D., Francis, P. T., & Lai, M. K. P. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105251 · Cited by 26 · see citing works
Effects of tart cherry and its metabolites on aging and inflammatory conditions: Efficacy and possible mechanisms
Mansoori, S., Dini, A., & Chai, S. C. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101254 · Cited by 21 · see citing works
The pharmacological management of Alzheimer's disease
Bishara, D., Sauer, J., & Taylor, D. M. (2015) · Progress in Neurology and Psychiatry · doi:10.1002/pnp.387 · Cited by 21 · see citing works
Cerebral transcriptome analysis reveals age-dependent progression of neuroinflammation in P301S mutant tau transgenic male mice
Kim, J., Selvaraji, S., Kang, S. W., Lee, W. T., Chen, C., Choi, H., Koo, E. H., Jo, D., Lim, K. L., Lim, Y.-A., et al. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.04.011 · Cited by 20 · see citing works
Terahertz Irradiation Improves Cognitive Impairments and Attenuates Alzheimer’s Neuropathology in the APPSWE/PS1DE9 Mouse: A Novel Therapeutic Intervention for Alzheimer’s Disease
Zhang, J., Chen, Y., Zhao, Y., Wang, P., Ding, H., Liu, C., Lyu, J., & Le, W. (2023) · Neuroscience Bulletin · doi:10.1007/s12264-023-01145-3 · Cited by 19 · see citing works
Association of Crocus sativus with Cognitive Dysfunctions and Alzheimer’s Disease: A Systematic Review
(2020) · Biointerface Research in Applied Chemistry · doi:10.33263/briac111.74687492 · Cited by 17 · see citing works
Breakdown of the blood–brain barrier: A mediator of increased Alzheimer's risk in patients with metabolic disorders?
Frank, C. J., & McNay, E. C. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.13074 · Cited by 15 · see citing works
Advances in Alzheimer’s disease therapeutics: biochemistry, exploring bioactive compounds and novel approaches
Atoki, A. V., Aja, P. M., Ondari, E. N., & Shinkafi, T. S. (2023) · International Journal of Food Properties · doi:10.1080/10942912.2023.2243050 · Cited by 19 · see citing works
Neuroprotective effect of diclofenac on chlorpromazine induced catalepsy in rats
Naeem, S., Najam, R., Khan, S. S., Mirza, T., & Sikandar, B. (2019) · Metabolic Brain Disease · doi:10.1007/s11011-019-00416-1 · Cited by 14 · see citing works
α-Synuclein and tau, two targets for dementia
Silva, M., Caro, V., Guzmán, C., Perry, G. L., Areche, C., & Cornejo, A. (2020) · Studies in natural products chemistry · doi:10.1016/b978-0-12-819483-6.00001-1 · Cited by 15 · see citing works
Small Molecule Rescue of ATXN3 Toxicity in C. elegans via TFEB/HLH-30
Fardghassemi, Y., Maios, C., & Parker, J. A. (2021) · Neurotherapeutics · doi:10.1007/s13311-020-00993-5 · Cited by 13 · see citing works
Effects of Current Psychotropic Drugs on Inflammation and Immune System
Bhatt, S., Dhar, A. K., Samanta, M. K., & Suttee, A. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-981-19-7376-5_18 · Cited by 11 · see citing works
The pharmacological management of Alzheimer's disease
Bishara, D. (2010) · Progress in Neurology and Psychiatry · doi:10.1002/pnp.151 · Cited by 10 · see citing works
Alzheimer diseases
Savonenko, A. V., Wong, P. C., & Li, T. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-85654-6.00022-8 · Cited by 8 · see citing works
Aging associated altered response to intracellular bacterial infections and its implication on the host
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Anti-inflammatory and immune therapy for Alzheimer’s disease: current status and future directions. Curr Neuropharmacol
Walker, D. (2016)
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Authors: Walker, D., & Lue, L.-F.
Affiliations: Banner Sun Health Research Institute (US)
Corresponding author: Walker, Douglas
ORCID: Walker, Douglas
Lue, Lih-Fen
Venue: Current Neuropharmacology
Publisher: Bentham Science Publishers Ltd.
Published: 2007-12-01
Volume: 5
Issue: 4
Pages: 232-243
ISSN: 1570-159X (ISSN-L)
DOI: 10.2174/157015907782793667
PMC: PMC2644496
OpenAlex: W2031392840
Cited by: 66
References: 210
Citations by year: 2026: 1 · 2025: 2 · 2023: 7 · 2022: 5 · 2021: 9 · 2020: 7 · 2019: 5 · 2018: 3 · 2017: 4 · 2016: 3 · 2015: 3 · 2014: 1 · 2013: 1 · 2012: 1
FWCI: 2.23
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Current Neuropharmacology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: Alzheimer's Association
National Institutes of Health
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: Alzheimer's disease, neuroinflammation, anti-inflammatory therapy, immunotherapy, microglia, reactive astrocytes, complement system, inflammatory cytokines, nonsteroidal anti-inflammatory drugs, amyloid clearance, microglial phagocytosis, anti-amyloid drugs, therapeutic target

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Anti-inflammatory and Immune Therapy for Alzheimers Disease: Current Status and Future Directions

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