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

The DOI matches its Crossref record; 210 of the 210 references it cites were found in a registry or an index.

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

Open access
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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Fig. (1) Potential interactions of Aβ peptide, vascular inflammation and cerebral inflammation in precipitating AD pathogenesis. In this scheme, peripheral disturbances (e.g. high levels of cholesterol, vascular inflammation, atherosclerosis) lead to compromise/inflammation of the cerebrovasculature. This will reduce transport of oxygen and glucose, creating conditions of oxidative stress that can increase Aβ production and aggregation, and neuronal stress directly. Deposition of Aβ can lead to cerebral inflammation, which can feedback to increase production of Aβ. The contribution of cerebral inflammation separate from Aβ to the progression of pathological changes is unclear, but inflammatory factors can mediate many of the neurotoxic events occurring in AD (tau hyperphosphorylation, synaptic loss, neuronal cell death).
Fig. (1) Potential interactions of Aβ peptide, vascular inflammation and cerebral inflammation in precipitating AD pathogenesis. In this scheme, peripheral disturbances (e.g. high levels of cholesterol, vascular inflammation, atherosclerosis) lead to compromise/inflammation of the cerebrovasculature. This will reduce transport of oxygen and glucose, creating conditions of oxidative stress that can increase Aβ production and aggregation, and neuronal stress directly. Deposition of Aβ can lead to cerebral inflammation, which can feedback to increase production of Aβ. The contribution of cerebral inflammation separate from Aβ to the progression of pathological changes is unclear, but inflammatory factors can mediate many of the neurotoxic events occurring in AD (tau hyperphosphorylation, synaptic loss, neuronal cell death).CC BY · PubMed Central
Fig. (2) When is the optimal stage of the disease to most effectively treat AD with anti-inflammatory agents. Figure shows progression of AD pathology, namely that the density of plaques, NFTs and activated microglia increase in the hippocampus/entorhinal cortex with decline in cognitive performance. MMSE – mini-mental status exam; the primary physician screening test of patient for cognitive decline. CDR – clinical dementia rating; a more detailed patient and informant assessment of cognitive decline.
Fig. (2) When is the optimal stage of the disease to most effectively treat AD with anti-inflammatory agents. Figure shows progression of AD pathology, namely that the density of plaques, NFTs and activated microglia increase in the hippocampus/entorhinal cortex with decline in cognitive performance. MMSE – mini-mental status exam; the primary physician screening test of patient for cognitive decline. CDR – clinical dementia rating; a more detailed patient and informant assessment of cognitive decline.CC BY · PubMed Central
Fig. (3) Potential targets that an “ideal AD therapeutic agent” might modulate to reduce the progression of AD pathology.
Fig. (3) Potential targets that an “ideal AD therapeutic agent” might modulate to reduce the progression of AD pathology.CC BY · PubMed Central
Fig. (4) Human microglia express mRNA for nicotinic acetylcholine receptor α7. Panel A –Reverse transcription-polymerase chain reaction showing expression by different isolates of human microglia of α7 nicotinic acetylcholine receptor mRNA (NAChRα7) (lanes 1-3). Panels B and C: show that human microglia do not express α2 (NAChRα2) or β4 (NAChRβ4) nicotinic acetylcholine receptor mRNA (lanes 1-3). As positive controls (panels A, B, C: lane 4), cDNA from a sample of differentiated SH-SY5Y neuronal-like cells showing positive expression of nicotinic acetylcholine receptor α7, α2 and β4.
Fig. (4) Human microglia express mRNA for nicotinic acetylcholine receptor α7. Panel A –Reverse transcription-polymerase chain reaction showing expression by different isolates of human microglia of α7 nicotinic acetylcholine receptor mRNA (NAChRα7) (lanes 1-3). Panels B and C: show that human microglia do not express α2 (NAChRα2) or β4 (NAChRβ4) nicotinic acetylcholine receptor mRNA (lanes 1-3). As positive controls (panels A, B, C: lane 4), cDNA from a sample of differentiated SH-SY5Y neuronal-like cells showing positive expression of nicotinic acetylcholine receptor α7, α2 and β4.CC BY · PubMed Central

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Metadata

Authors
Walker, D., & Lue, L.-F.
Affiliations
Banner Sun Health Research Institute (US)
Corresponding author
Walker, Douglas
ORCID
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
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
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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