TLDR
Reelin is a glycoprotein crucial for brain development and function, influencing neuronal migration, synaptic plasticity, and cognitive processes. Understanding the pathways regulating Reelin and the effects of various phytochemicals on its expression can offer insights into potential therapeutic strategies for cognitive decline and neurodegenerative diseases. However, given the PI3K-Akt pathway’s role in both brain health and cancer, careful consideration is necessary when targeting Reelin upregulation, especially in cancer patients.
Role of Reelin in the Brain
Neuronal Migration and Positioning: During brain development, Reelin is essential for proper neuronal layering in the cortex and hippocampus.
Synaptic Plasticity and Function: In the adult brain, Reelin promotes synaptic plasticity, crucial for learning and memory.
Cognitive Health: Adequate Reelin levels are associated with cognitive resilience, while reduced Reelin is linked to cognitive decline and neurodegenerative diseases like Alzheimer's.
Epigenetic Modifications: Histone acetylation and reduced DNA methylation at the RELN promoter enhance its expression.
Environmental and Lifestyle Factors
Physical Exercise: Promotes neurogenesis and synaptic plasticity, increasing Reelin levels.
Cognitive Stimulation: Learning and complex tasks enhance Reelin expression.
Dietary and Nutritional Factors
Omega-3 Fatty Acids: These support Reelin expression.
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Phytochemicals Upregulating Reelin
Curcumin
Mechanism: Antioxidant and anti-inflammatory effects, modulation of CREB and BDNF pathways.
Resveratrol
Mechanism: Activation of sirtuins, reduction of oxidative stress and inflammation.
Epigallocatechin Gallate (EGCG)
Mechanism: Antioxidant properties, modulation of PI3K-Akt pathway.
Quercetin
Mechanism: Antioxidant and anti-inflammatory effects, modulation of neuroprotective pathways.
Pterostilbene
Mechanism: Similar to resveratrol, neuroprotective through antioxidant and anti-inflammatory actions.
Luteolin
Mechanism: Anti-inflammatory and antioxidant properties, enhancement of Reelin expression.
Hesperidin
Mechanism: Neuroprotective effects through anti-inflammatory and antioxidant actions.
Potential Risks of Reelin Upregulation
PI3K-Akt Pathway Activation: While beneficial for neuronal survival and plasticity, activation of this pathway can contribute to tumor growth and survival in cancer.
Cancer Considerations: Upregulating Reelin might exacerbate cancer by enhancing the PI3K-Akt pathway. However, many phytochemicals that upregulate Reelin also exhibit anti-cancer properties so perhaps it's not entirely that important.
Luteolin: Protects PP2A from oxidative stress-induced inhibition.
Resveratrol: Enhances PP2A activity by modulating its methylation state.
Resulting HyperphosphorylationCumulative Effect: Increased kinase activity (GSK-3β and CDK5) and decreased phosphatase activity (PP2A) lead to excessive tau hyperphosphorylation.
Impact on Tau: Hyperphosphorylated tau detaches from microtubules, causing microtubule destabilization and disrupted intracellular transport.
Phytochemical Modulation:
Curcumin, Resveratrol, EGCG, Quercetin, Luteolin, Hesperidin: These phytochemicals inhibit kinases, activate phosphatases, and reduce oxidative stress, mitigating tau hyperphosphorylation and its detrimental effects on neurons.
I was actually trying to indicate that Alzheimers acts like cancers - standard pathways are mutated away from and disregarded by the Alzheimers/cancerous taus. In any cancer, your body stops reaponsing to multiple signals for cell regulation. Thus enabling tau production and retention in a system with damaged tau production may be cou ter productive.
As seen in some od the studies of Alzheimers resistant peoples, they produce a form of Reelin that is free of the tau pathways, thus are not inhibited when the taus go rogue.
Alzheimer’s Disease: DNA methylation and histone modification.
Cancer: Activation of oncogenes or silencing of tumor suppressor genes.
Cell Cycle and Apoptosis:
Abnormal regulation of cell cycle and apoptosis pathways.
Alzheimer’s Disease: Contributes to neuronal death.
Cancer: Leads to uncontrolled cell proliferation and resistance to apoptosis.
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Shared phytochemicals that modulate progression
Curcumin
Cancer: Curcumin, found in turmeric, has been shown to have anti-inflammatory, antioxidant, and anticancer properties. It can inhibit the growth of cancer cells, induce apoptosis (programmed cell death), and inhibit angiogenesis (formation of new blood vessels that feed tumors).
Alzheimer’s: Curcumin has neuroprotective properties, including reducing amyloid plaque accumulation, inhibiting tau protein aggregation, and reducing oxidative stress and inflammation in the brain.
Resveratrol
Cancer: Resveratrol, found in grapes, berries, and peanuts, exhibits anticancer properties by inhibiting cell proliferation, inducing apoptosis, and modulating various signaling pathways involved in cancer progression.
Alzheimer’s: Resveratrol has neuroprotective effects, including reducing beta-amyloid plaque formation, protecting against oxidative stress, and improving mitochondrial function.
Epigallocatechin Gallate (EGCG)
Cancer: EGCG, a catechin found in green tea, has strong antioxidant properties and can inhibit cancer cell growth, induce apoptosis, and modulate signaling pathways involved in cancer development.
Alzheimer’s: EGCG can reduce the formation of beta-amyloid plaques, protect neurons from oxidative damage, and improve cognitive function.
Quercetin
Cancer: Quercetin, found in onions, apples, and berries, has been shown to inhibit cancer cell proliferation, induce apoptosis, and inhibit angiogenesis. It also has anti-inflammatory and antioxidant properties.
Alzheimer’s: Quercetin has neuroprotective effects, including reducing oxidative stress, inhibiting beta-amyloid aggregation, and protecting neurons from toxicity.
Sulforaphane
Cancer: Sulforaphane, found in cruciferous vegetables like broccoli, has potent anticancer effects. It can inhibit cancer cell growth, induce phase II detoxification enzymes, and promote apoptosis.
Alzheimer’s: Sulforaphane has been shown to reduce oxidative stress, inhibit the formation of beta-amyloid plaques, and protect against neuronal damage.
Luteolin
Cancer: Luteolin, found in celery, parsley, and various herbs, exhibits anticancer properties by inhibiting cell proliferation, inducing apoptosis, and inhibiting angiogenesis. It also has anti-inflammatory and antioxidant effects.
Alzheimer’s: Luteolin can reduce neuroinflammation, inhibit beta-amyloid formation, and protect against oxidative stress, contributing to its neuroprotective effects.
Role of Reelin in the Brain
Routes of Reelin Activation
Neuronal Activity
Neurotransmitters and Neurotrophic Factors
Transcriptional and Epigenetic Regulation
Environmental and Lifestyle Factors
Dietary and Nutritional Factors
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Phytochemicals Upregulating Reelin
Curcumin
Resveratrol
Epigallocatechin Gallate (EGCG)
Quercetin
Pterostilbene
Luteolin
Hesperidin
Potential Risks of Reelin Upregulation
Note that Alzheimer's tau degredation acts like a cancer by "targeting" (for lack of a better word) Reelin-producing neurons.
correct but the very same phytochemicals help with that as well!
Pathway of Tau Hyperphosphorylation
1. Normal Tau Function Tau protein normally binds to and stabilizes microtubules, essential for neuronal structure and intracellular transport.
2. Kinase Activation Glycogen Synthase Kinase 3 Beta (GSK-3β)
Activation: GSK-3β is activated through insulin signaling dysregulation, Wnt signaling, and inflammatory cytokines.
Phytochemical Modulation:
Cyclin-Dependent Kinase 5 (CDK5)
3. Phosphatase Inhibition Protein Phosphatase 2A (PP2A)
Resulting Hyperphosphorylation Cumulative Effect: Increased kinase activity (GSK-3β and CDK5) and decreased phosphatase activity (PP2A) lead to excessive tau hyperphosphorylation.
Mechanistic Insights and Phytochemical Modulation
GSK-3β Activation
CDK5 Activation
PP2A Inhibition
I was actually trying to indicate that Alzheimers acts like cancers - standard pathways are mutated away from and disregarded by the Alzheimers/cancerous taus. In any cancer, your body stops reaponsing to multiple signals for cell regulation. Thus enabling tau production and retention in a system with damaged tau production may be cou ter productive.
As seen in some od the studies of Alzheimers resistant peoples, they produce a form of Reelin that is free of the tau pathways, thus are not inhibited when the taus go rogue.
I agree, that is an apt comparison. Here is some similarities if found between the two.
Clinical Similarities Between Cancer and Alzheimer’s Disease
Protein Misfolding and Aggregation:
Dysregulated Pathways:
Genetic Mutations:
Chronic Inflammation:
Oxidative Stress:
Cellular Senescence:
Epigenetic Changes:
Cell Cycle and Apoptosis:
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Shared phytochemicals that modulate progression
Curcumin
Resveratrol
Epigallocatechin Gallate (EGCG)
Quercetin
Sulforaphane
Luteolin