Thanks dfwl,
This is more like what Dr J was referencing concerning Alzheimer’s and CCR5/ccl5 axis. Mighty and my thoughts were much more temporal window related. This is also more recent, last Fall, and a summary of many research avenues.
For those interested but can’t read the entire paper, I’d like to add a couple quotes.
“ patients with AD, which was shown to be associated with Aβ deposition (42). One study found that RANTES level was significantly higher in patients with AD than in control subjects and was positively correlated with IL-6 and TNF-α levels (43), implying that CCL5 contributes to AD pathogenesis by mediating the inflammatory response and is a potential biomarker for early disease diagnosis”
“ n addition to the immune response, CCR5 is involved in neurotransmission, brain development, and learning and memory, among other functions (25). CCR5 is expressed throughout the CNS at all stages of development from embryo to adult, but the distribution varies across brain areas, which may be related to its different functions in different parts of the brain (26, 27). CCR5 is expressed in glial cells and neurons in the cerebral cortex, hippocampus, basal nuclei, and thalamus, and the expression level was shown to increase from birth to 9 months of age, and it was also observed in adult neural progenitor cells (28), which indicates that CCR5 is involved in neural development”
“ a study has shown that CCR5 may affect normal learning and memory by acting on the cyclic AMP response element-binding (CREB) protein pathway (30). CCR5 was also shown to reduce the plasticity of neurons in the cerebral cortex and hippocampus-dependent learning and memory. Therefore, the effect of activating or inhibiting CCL5/CCR5 axis on memory may be opposite, and some studies have also proved this. Inhibition of CCR5 increased MAPK/CREB signaling and enhanced memory, whereas CCR5 overexpression resulted in memory impairment and decreased plasticity (31).”
Just following this quote in the paper is the reference you shared which I believe describes the section of Mightys paper in regards to aging mice and knocking out CCR5 by maravovic.
“ CCR5 is significantly upregulated in reactive microglia in patients with AD, which was shown to be associated with Aβ deposition (42). One study found that RANTES level was significantly higher in patients with AD than in control subjects and was positively correlated with IL-6 and TNF-α levels (43), implying that CCL5 contributes to AD pathogenesis by mediating the inflammatory response and is a potential biomarker for early disease diagnosis. Genome-wide analyses have also identified CCR5 as one of the major hub genes in AD (44). In a rat model of lipopolysaccharide (LPS)-induced neuroinflammation, the CCR5 antagonist D-Ala-peptide T-amide reduced the number of microglia and astrocytes in the hippocampus as well as astrocyte hypertrophy, and microglia had slender processes similar to those observed in the nonactivated state (45). In CCR5−/− mice, Aβ1–40 overexpression in hippocampus decreased the aggregation of astrocytes and microglia and alleviated cognitive impairment and synaptic dysfunction; these effects were associated with the downregulation of cyclooxygenase-2, iNOS, and nuclear factor κB (46). These findings suggest that blocking CCR5 can reduce neuroinflammation, which may be an effective therapeutic strategy for AD.”
CONCLUSION
There is ample evidence that the immune response is involved in the pathogenesis of AD; the neuroinflammation hypothesis is highly attractive and is a powerful complement to the Aβ and tau protein hypotheses. During neuroinflammation, Aβ deposition activates astrocytes and microglia, with the latter transforming from a protective to a proinflammatory phenotype. Acute inflammation at the early stage is beneficial for clearing Aβ and repairing neuronal damage. However, with the progression of AD, microglia and astrocytes secrete proinflammatory cytokines and chemokines, leading to excessive and uncontrolled inflammation and neuron death. The CCL5/CCR5 axis plays an important role in learning, memory, neuroinflammation, and AD pathogenesis; however, the mechanistic details of CCL5/CCR5 axis in AD have not been fully elucidated and some of the existing evidence is contradictory. Even population-based studies on the distribution of the CCR5Δ32 allele have shown no association between CCL5/CCR5 and AD development. A reason for these conflicting findings may be differences in animal models and populations, but it is also possible that CCR5 has as-yet unidentified functions in the CNS. More studies are needed to explore the specific role of the CCL5/CCR5 signaling axis in AD pathogenesis in order to determine whether it can serve as a therapeutic target in treatment of AD. In addition, we believe that it will also be a potentially valuable idea to expand the scope of exploring CCL5/CCR5 axis to other neurodegenerative diseases.
I’d like to emphasize I sentence from the above conclusion.
“ However, with the progression of AD, microglia and astrocytes secrete proinflammatory cytokines and chemokines, leading to excessive and uncontrolled inflammation and neuron death.”
Sound familiar?
This is more like what Dr J was referencing concerning Alzheimer’s and CCR5/ccl5 axis. Mighty and my thoughts were much more temporal window related. This is also more recent, last Fall, and a summary of many research avenues.
For those interested but can’t read the entire paper, I’d like to add a couple quotes.
“ patients with AD, which was shown to be associated with Aβ deposition (42). One study found that RANTES level was significantly higher in patients with AD than in control subjects and was positively correlated with IL-6 and TNF-α levels (43), implying that CCL5 contributes to AD pathogenesis by mediating the inflammatory response and is a potential biomarker for early disease diagnosis”
“ n addition to the immune response, CCR5 is involved in neurotransmission, brain development, and learning and memory, among other functions (25). CCR5 is expressed throughout the CNS at all stages of development from embryo to adult, but the distribution varies across brain areas, which may be related to its different functions in different parts of the brain (26, 27). CCR5 is expressed in glial cells and neurons in the cerebral cortex, hippocampus, basal nuclei, and thalamus, and the expression level was shown to increase from birth to 9 months of age, and it was also observed in adult neural progenitor cells (28), which indicates that CCR5 is involved in neural development”
“ a study has shown that CCR5 may affect normal learning and memory by acting on the cyclic AMP response element-binding (CREB) protein pathway (30). CCR5 was also shown to reduce the plasticity of neurons in the cerebral cortex and hippocampus-dependent learning and memory. Therefore, the effect of activating or inhibiting CCL5/CCR5 axis on memory may be opposite, and some studies have also proved this. Inhibition of CCR5 increased MAPK/CREB signaling and enhanced memory, whereas CCR5 overexpression resulted in memory impairment and decreased plasticity (31).”
Just following this quote in the paper is the reference you shared which I believe describes the section of Mightys paper in regards to aging mice and knocking out CCR5 by maravovic.
“ CCR5 is significantly upregulated in reactive microglia in patients with AD, which was shown to be associated with Aβ deposition (42). One study found that RANTES level was significantly higher in patients with AD than in control subjects and was positively correlated with IL-6 and TNF-α levels (43), implying that CCL5 contributes to AD pathogenesis by mediating the inflammatory response and is a potential biomarker for early disease diagnosis. Genome-wide analyses have also identified CCR5 as one of the major hub genes in AD (44). In a rat model of lipopolysaccharide (LPS)-induced neuroinflammation, the CCR5 antagonist D-Ala-peptide T-amide reduced the number of microglia and astrocytes in the hippocampus as well as astrocyte hypertrophy, and microglia had slender processes similar to those observed in the nonactivated state (45). In CCR5−/− mice, Aβ1–40 overexpression in hippocampus decreased the aggregation of astrocytes and microglia and alleviated cognitive impairment and synaptic dysfunction; these effects were associated with the downregulation of cyclooxygenase-2, iNOS, and nuclear factor κB (46). These findings suggest that blocking CCR5 can reduce neuroinflammation, which may be an effective therapeutic strategy for AD.”
CONCLUSION
There is ample evidence that the immune response is involved in the pathogenesis of AD; the neuroinflammation hypothesis is highly attractive and is a powerful complement to the Aβ and tau protein hypotheses. During neuroinflammation, Aβ deposition activates astrocytes and microglia, with the latter transforming from a protective to a proinflammatory phenotype. Acute inflammation at the early stage is beneficial for clearing Aβ and repairing neuronal damage. However, with the progression of AD, microglia and astrocytes secrete proinflammatory cytokines and chemokines, leading to excessive and uncontrolled inflammation and neuron death. The CCL5/CCR5 axis plays an important role in learning, memory, neuroinflammation, and AD pathogenesis; however, the mechanistic details of CCL5/CCR5 axis in AD have not been fully elucidated and some of the existing evidence is contradictory. Even population-based studies on the distribution of the CCR5Δ32 allele have shown no association between CCL5/CCR5 and AD development. A reason for these conflicting findings may be differences in animal models and populations, but it is also possible that CCR5 has as-yet unidentified functions in the CNS. More studies are needed to explore the specific role of the CCL5/CCR5 signaling axis in AD pathogenesis in order to determine whether it can serve as a therapeutic target in treatment of AD. In addition, we believe that it will also be a potentially valuable idea to expand the scope of exploring CCL5/CCR5 axis to other neurodegenerative diseases.
I’d like to emphasize I sentence from the above conclusion.
“ However, with the progression of AD, microglia and astrocytes secrete proinflammatory cytokines and chemokines, leading to excessive and uncontrolled inflammation and neuron death.”
Sound familiar?
10
