o Long-Term Potentiation (LTP)
Perhaps the most significant process in learning and memory is known as Long-Term Potentiation (LTP). LTP is the increase in strength of the synaptic signal between communicating neurons, and is maintained for a long period of time. The encoding of memories is enhanced by the increase in synaptic strength expressed in LTP. Based on these observations, LTP is believed to be of great importance in learning and memory formation. Conversely, abnormal synaptic functioning (including dysfunction of LTP) account for the cognitive deficits seen in many brain and memory disorders. Declines in hippocampus synaptic function is a normally a prelude to neurodegenerative diseases such as Alzheimer's Disease. Neuro connections and synpatic signals decline with age. When we can't precisely remember something, or say it is on the "tip of our tongue", it is most likely the result of the decreased strength of the neuro connection.
Yellow natural ingredients have been shown in research studies to enhance LTP including luteolin(1), and fisetin(2). Also, curcumin increases levels of the enzyme CaMKII in the hippocampus, which can independently induce LTP and improve learning and memory (3). Furthermore, curcumin has been demonstrated to restore LTP functionality which had been impaired by amyloid affected hippocampus neurons.(4) In addition to enhancing synaptic signaling (LTP), luteolin was also shown to have a protective effect on learning and memory, by restoring lost LTP function in animals experimentally induced to emulate neurodegenerative diseases.
o Enhancing the Neuron Activity Levels
• Adult Neurogenesis (New brain Cells)
• Neurotrophic Factors (Supporting neuron growth, development & survival)
Adult neurogensis - is the formation of new brain cells from adult neural stem cells (neuroprogenitor cells). The hippocampus, the primary area of the brain important for learning, recall and memory, can be induced for new neuron production. Such neurons can be integrated into the neuron network and enhance memory functions. (5) Administration of curcumin has been shown to activate pathways in the brain associated with neuron plasticity, resulting in a significant number of new neurons in the hippocampus.(6) Apigenin also is capable of neurogenesis.(7)
Neurotrophic Factors – Are promoters of health and activity of neurons in the brain. The yellow brain enhancers fisetin, luteolin and curcumin all stimulate neurotrophic activity. Luteolin has been shown to induce neurite outgrowth in neurons and increase antioxidant protection of the cell.(8) Neurite outgrowth is an important neuron characteristic associated with memory enhancement. Fisetin’s neurotrophic effects include increases in neuron survival and increasing the length of the neurite.(9) Pterostilbene, a non-yellow analogue of resveratrol, also mobilizes neurotrophic factors by enhancing working memory. Research with aged rats showed a correlation between memory and pterostilbene levels in the hippocampus region.(25) Studies also determine that another yellow natural promoter of neurite outgrowth is quercetin. The flavonoid quercetin stimulates nerve growth factor (NGF)-induced neurite outgrowth in support of memory improvement and brain function. (27)
NeuroProtection | Reversing Neuroinflammation
o Blood Brain Barrier
Protecting the brain requires maintaining the integrity of the Blood Brain Barrier which is affected during periods of neuroinflammation. The blood brain barrier is critical for blocking harmful substances from entering the brain via the bloodstream. However, this barrier becomes disrupted during periods of inflammation, leading to brain injury and other potential diseases of the brain. In studies, fisetin, apigenin and luteolin acted to inhibit NF-kB inflammatory transcription factor, reducing inflammatory components, thereby helping to maintain the integrity of the blood-brain-barrier.(10)
o Nrf2 – Antioxidant regulator for Neuron Protection
The extremely important endogenous antioxidant system, known as Nrf2, plays a frontline role in ensuring the protection of the neurons against oxidative stress and neuronal cell death. Many of the anti-aging yellow extracts induce the activation of Nrf2, and therefore supports the health and survival of the neurons in the brain. Nrf2 is the major transcription factor for the Antioxidant Response Element (ARE). In fact HO-1, Heme oxygenase-1, is a very important antioxidant enzyme for modulating the inflammatory response and is activated through Nrf2. Current research is examining the potential for HO-1 (via Nrf2 activation) for targeting neuroinflammation in neurodegenerative diseases.(21) Curcumin, fisetin, ginger, EGCG and luteolin are powerful inducers of HO-1.(11, 22, 23, 24 8)
o Inhibition of Common Neurodegenerative Inflammatory Pathway – through the Modulating Microglial Activation
Almost all neurodegenerative diseases have in common microglial activated inflammation. Microglia is a component of the immune system, but the chronic overexpression of microglia generates incessant amounts of constant inflammation that slowly degenerates the brain. Apigenin and luteolin have been found to be very effective in suppressing the chronic over expression of microglia activators, thereby conferring potent anti-inflammatory protection to the neurons.(18, 19) Researchers suggest that apigenin and luteolin may have disease modifying (therapeutic) effect in neuroinflammatory diseases, such as Alzheimer’s Disease.
o Advanced Glycation End (AGE) Products – Delaying Neuroinflammatory Disease Progression by Inhibition of AGE Induced Inflammation
AGE products are caused by the irreversible binding of sugar in the blood to protein. The result is a dysfunctional distorted protein, which no only can’t function normally. Furthermore, AGEs become a significant source of pro-inflammatory molecules – including TNF-alpha and inducible Nitric Oxide. In the case of neurodegenerative diseases, such as Alzheimer’s, AGEs accumulate on the amyloid plaques, and accelerate the progression of the disease by increasing inflammation levels. Apigenin was shown to be a potent inhibitor of AGE-induced NO and TNF-alpha production. The authors concluded that plant derived polyphenols, including apigenin, may be of therapeutic value in slowing the progression of AGE-mediated neuroinflammatory diseases.(16)
o Protection of Hippocampus Neuron Cells Against Stress Induced Cellular Death.
Endoplasmic Recticulum (ER) stress is an important element in neurodegenerative diseases. Stress inducers are a potent degenerative factor for neurons in the hippocampus. Apigenin was shown to reduce neuron cellular death in the hippocampus by modulating the effect of ER stress inducers.(5)
Amyloid Beta (Abeta) | Alzheimer’s Disease Progression
o Curcumin - Neurodegeneration and Alzheimer’s Disease.
One of the most potentially powerful natural spices for the protection of the brain is yellow pigment curcumin. In India, where turmeric (the spice containing curcumin) is widely used as a seasoning, there is a significantly lower incidence of Alzheimer’s Disease than in the United States.
(1) Curcumin is a powerful inducer of heme oxygenase 1 and Phase II detoxification enzymes in neurons. Each of these antioxidants provides significant protection of the neuron against oxidative stress, dysfunction and cellular senescence / neuronal death.(11)
(2) Alzheimer’s Disease (AD) is largely driven by the formation of amyloid-beta (Abeta) plaques in the brain. Curcumin has been shown, in mice models of AD, to decrease levels of Abeta plaques by attenuating the maturation of the Abeta precursor protein.(12)
(3) Curcumin also binds to Abeta, preventing the formation amyloid aggregates and fibrils. Therefore, this disaggregation effect of curcumin of Abeta helps reduce amyloid plaque formation burden and may slow the progression of the disease. (13)
(4) In AD mice models, curcumin has been shown to improve memory of the mice. Curcumin also inhibited neuron cell death and reduced changes to the hippocampus area (where memory and learning is most critical). (20)
(5) Curcumin and vitamin D3 work synergistically to stimulate the immune system for clearance of amyloid-beta in Alzheimer’s patients. The immune system of the Alzheimer’s patient is defective and unable to clear the amyloid-beta toxins. Curcumin and vitamin D3 enhance macrophage activity, to facilitate the amyloid-beta removal.(26)
o Fisetn and Luteolin - Inhibition of Amyloid Beta (Abeta) Fibril Formation
In research studies, fisetin and luteolin have been shown to inhibit the aggregation of amyloid beta protein.(14, 29) The inhibitory effect of Abeta fibril aggregation by fistein and luteolin may contribute to development of new therapeutic drugs for Alzheimer’s.
o Apigenin – Neurovascular and Cholinergic Protective Effect Against Amyloid Beta (Abeta)
Administration of apigenin to laboratory mice showed that apigenin conferred significant protection against Abeta toxicity through robust safeguarding of the neurovascular coupling function. As such, apigenin administrated to Abeta induced amnesic mice improved cerebral blood flow, reduced neurovascular oxidative damage, and improvement the levels of acetylcholine in the brain.(15) Apigenin has also been shown to protect the membranes of the neurons against damage by the amyloid beta plaques. Disruption of membrane integrity leads to synpatic dysfunction and neuron death.(28)
o EGCG and Luteolin – Reducing Amyloid Beta Induced Mitochondria Dysfunction
Amyloid in Alzheimer’s Disease is associated with mitochondrial dysfunction. Mitochondria are the energy producing components of the cells, and must be operationally functional to ensure survival of the cell. It is thought that the onset and progression of Alzheimer’s to be closely linked to effect of the amyloid on the mitochondria. In a laboratory study it was demonstrated that EGCG and luteolin acted as “multipotent therapeutic agents” by reducing toxic levels of Amyloid beta in the brain, in addition to restoring mitochondria function. (17)
o Gingerol (Ginger Extract) Attenuates Amyloid Beta Neuron Death by Fortifying Antioxidant Cellular Defense System
Activation of Nrf2 by gingerol increased levels of antioxidant enzyme heme oxygenase-1 (HO-1). Pretreatment of cell cultures prior to administering Abeta, protected the cells against amyloid induced cellular toxicity and cellular death. (23)
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