Herbal Extracts - Neurogenesis & Recovery of Cognition Impairments

Aging of the brain involves the loss of neurons (hippocapmus shrinkage), loss of synapse integrity between neurons, build-up of toxic amyloid proteins, neuron tangles, defects in blood flow  and chronic inflammation. Under normal age progression, these events do not happen over night and may take years before impairments in cognition become noticed.

Ultimate anti-aging strategies for the brain and memory should target the progressive decline of the brain and promote reversal and recovery of some cognition impairments.

Emerging research in the study of herbal ingredients show their tremendous potential use in mitigating the decline in brain function with age.

• NEUROGENESIS - is the formation of new neurons, specifically in the hippocampus area in the brain.The hippocampus is essential in providing the capacity for memory and learning. Dementia and Alzheimer's disease are associated with brain shrinkage which is correlated to the loss of neurons in the hippocampus. The formation of new neurons may reverse brain shrinkage.

                    Herbs and Extracts

•  Andrographolide - As an extract from Andrographis Paniculata. Lab research has shown stimulation of neurogenesis in the hippocampus by andorgrapholide. Specifically " increased cell proliferation and the density of immature neurons in the dentate gyrus." (1) The dentate gyrus is an area of the hippocampus involved in memory formation.
• Centella asiatica - Acts as a potent memory enhancer, via  increasing hippocampus neurogenesis and support for brain tissue regeneration. (2)
• Baicalin (3)
• Panax Ginseng (4)
  
• Curcumin (5)
• Epimedium (Icariin)  (6)
• Apigenin (7)
  

• BRAIN TISSUE REGENERATION. While in the same theme as neurogenesis, brain tissue regeneration refers to the enhancement and regeneration of critical neuron structures - axons and dendrites. Dendrites transmit signals from the synapse to the body of the neuron. Axons transmit signals away from the body of the neuron and are covered with a myelin sheath which increase speed of the impulse providing rapid impulse transmission. Aging degenerates the structural integrity of dendrites and axon/myelin complex.
  

                     Herbs and Extracts

•  Centella asiatica - Improves structural integrity of axons / myelination and proliferation of dendritic branching and length. Such improvements have been shown to enhance learning and improve memory. (8) Centella asiatica also has been shown to improve learning and memory in normal lab mice.
• Luteolin - Baicalin - promote neuronal survival and neuron differentiation through the outgrowth of neurites  (axons and dendrites) from the neuron.(9.10)
• Rosemary (Carnosic Acid) - Strongly promotes neurite outgrowth as a function of powerful Nrf2 activity. Suppressed Nrf2 activation suppresses neuron differentiation.(11)

• RECOVERY OF COGNITIVE IMPAIRMENT - the  to reversal of certain functional impairments which may improve cognitive function. Many research animal models for cognitive impairment are characteristically similar to Alzheimer's disease (AD). Impairment usually involves cerebral vascular disease, synaptic dysfunction. and more.

          Herbs and Extracts

• Andrographolide - Impairment of synaptic function between neurons plays a significant role in the loss of cognitive function. This is seen in the progression of AD. In research animals with AD-like cognitive disease, the treatment of andrographolide over a 3 month span imporved synaptic function and protected important synaptic proteins.
• Furthermore, andrographolide has been shown to reduce inflammation in the brain and levels of pathological tau protein and beta amyloid in animal models.(12)
• Andrographolide reduces inflammation and dysfunction of the cerebral endothelial cells, which may affect vascular flow to the brain.(13)
• Centella asiactica - in senescence-accelerated lab mice, which had accelerated aging of the brain, administration of centella asiatica significantly improved synaptic plasticity and reduced beta amyloid build-up. Such treated mice showed significant benefits in memory and learning. (14)

• NEUROPROTECTION - AMYLOID & NON-AMYLOID (α-synuclein) TOXICITY | CHRONIC INFLAMMATION - The aging brain is under continual assault and must be protected to prevent cognitive decline and loss of neurons. Key areas of protection include the build-up of amyoid plaques which are toxic to neurons and synapses. Moreover, chronic inflammation in the brain accelerates destruction of the brain and is believed to be the facilitator of degenerative brain diseases.
• Centella asiatica (15)
  
• Epimedium (Icariin)(16,17)
• Apigenin and luteolin (18,19)
  
• Baicalin (20)
  
• Schisandra (21)
• Rosemary (Carnosic Acid)(22)

• REVERSES INSULIN RESISTANCE IN BRAIN NEURONS - Aging brains become increasingly incapable of using glucose as an energy source. Without this energy neurons age faster and die. Reversing the insulin resistance maintains healthy neurons. Brain insulin resistance is associated with Alzheimer's Disease.
• Further reduction in glucose availability is caused by methylglyoxal - a powerful intermediate in the formation of Advanced Glycation End Products (AGEs).
• Curcumin - Improves insulin sensitivity in neurons. (23)
• Sulforaphane - Reverses reduction of glucose uptake by neurons caused by methylglyoxal (a precusor of advanced glycation end products). Sulforaphane also normalizes brain-derived neurotrophic factor (BDNF) signaling, which is critical for maintaining brain function. BDNF pathways are disrupted in Alzheimer's Disease. (24)

YELLOW LONGEVITY

YELLOW NATURALLY

MEMORY ACTION

XGEVITY

LONGEVITY NATURALLY

REFERENCES:

NEUROGENESIS

(1)   Varela-Nallar L, et al. Andrographolide Stimulates Neurogenesis in the Adult Hippocampus. Neural Plast, 2015.

(2)  Sirichoat A, et al. Effects of Asiatic Acid on Spatial Working Memory and Cell Proliferation in the Adult Rat Hippocampus. Nutrients. 2015 Oct 5

(3) Zhang K, et al. Baicalin promotes hippocampal neurogenesis via SGK1- and FKBP5-mediated glucocorticoid receptor phosphorylation in a neuroendocrine mouse model of anxiety/depression. Sci Rep. 2016 Aug 9

(4) Jiang B, et al.  Antidepressant-like effects of ginsenoside Rg1 are due to activation of the BDNF signalling pathway and neurogenesis in the hippocampus. Br J Pharmacol. 2012 Jul;

 (5) Pluta R, et al. Neurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin? Folia Neuropathol. 2015

(6) Li F, et al. Icariin decreases both APP and Aβ levels and increases neurogenesis in the brain of Tg2576 mice. Neuroscience. 2015 Sep 24

(7) Taupin P. Apigenin and related compounds stimulate adult neurogenesis. Mars, Inc., the Salk Institute for Biological Studies: WO2008147483. Expert Opin Ther Pat. 2009 Apr

BRAIN TISSUE REGENERATION

(8) Yogeswarin L, et al. Recent Updates in Neuroprotective and Neuroregenerative Potential of Centella asiatica. Malays J Med Sci 2016 Jan.

(9) Chen PY, et al. Up-Regulation of miR-34a Expression in Response to the Luteolin-Induced Neurite Outgrowth of PC12 Cells. J Agric Food Chem. 2015 Apr

(10) Li M, et al. Neuronal differentiation of C17.2 neural stem cells induced by a natural flavonoid, baicalin. Chembiochem. 2011 Feb 11;

(11) Kosaka K, et al. Role of Nrf2 and p62/ZIP in the neurite outgrowth by carnosic acid in PC12h cells. J Biochem. 2010 Jan;

RECOVERING COGNITIVE DYSFUNCTION

(12) Rivera DS, et al. Andrographolide recovers cognitive impairment in a natural model of Alzheimer's disease (Octodon degus). Neurobiol Aging. 2016 Jul 5

(13) Chang CC, et al. Andrographolide, a Novel NF-κB Inhibitor, Inhibits Vascular Smooth Muscle Cell Proliferation and Cerebral Endothelial Cell Inflammation. Acta Cardiol Sin. 2014 Jul;

(14) Xing L, et al. Beneficial effects of asiaticoside on cognitive deficits in senescence-accelerated mice. Fitoterapia. 2013 Jun.

NEUROPROTECTION - AMYLOID TOXICITY AND INFLAMMATION

(15) Gray NE, et al. Centella asiatica Attenuates Amyloid-β-Induced Oxidative Stress and Mitochondrial Dysfunction. J Alzheimers Dis. 2015

(16) Zhang L, et al. Icariin reduces α-synuclein over-expression by promoting α-synuclein degradation. Age (Dondr.) 2015 Aug

(17) Chen YJ, et al. Neuroprotective Effects of Icariin on Brain Metabolism, Mitochondrial Functions, and Cognition in Triple-Transgenic Alzheimer's Disease Mice. CNS Neurosci Ther, 2016 Jan

(18) Dirscherl K, et al. Luteolin triggers global changes in the microglial transcriptome leading to a unique anti-inflammatory and neuroprotective phenotype. J Neuroinflammation 2010 Jan

(19) Rezai-Zedeh K, et al. Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression. J Neuroinflammation. 2008 Sep

(20) Chen C, et al. Baicalin attenuates alzheimer-like pathological changes and memory deficits induced by amyloid β1-42 protein.  Metab Brain Dis. 2015 Apr

(21) Song F, et al. Schizandrin A Inhibits Microglia-Mediated Neuroninflammation through Inhibiting TRAF6-NF-κB and Jak2-Stat3 Signaling Pathways. PLoS One. 2016 Feb 26;

(22) Habtemariam S. The Therapeutic Potential of Rosemary (Rosmarinus officinalis) Diterpenes for Alzheimer's Disease. Evid Based Complement Alternat Med, 2016

REVERSES BRAIN INSULIN RESISTANCE IN BRAIN NEURONS

(23) Feng HL, et al. Curcumin ameliorates insulin signalling pathway in brain of Alzheimer's disease transgenic mice. Int J Immunopathol. 2016 Jul 27

(24) Angeloni C, et al. Neuroprotective effect of sulforaphane against methylglyoxal cytotoxicity. Chem Res Toxicol, 2015 Jun 15

Chemicals and Pesticides - Impact on Brain Aging & Neurodegeneration

Aging and degeneration of the brain is affected by both internal and environmental factors. This includes the pesticide residue found on foods. Disruption of brain homeostasis, associated with aging,  results in amyloid plaques and neuro fibrillary tangles. However, the wide pervasiveness of chemicals, including pesticides, in our modern age are now suspected of playing a major role in neurodegenerative diseases. An important source of chemicals are the pesticides which are pervasive in our environment and food.

Chemicals have been associated with Parkinson's Disease, autism, Alzheimer's Disease and Huntington's Disease. In fact, environmental chemicals affect the brain in a similar manner as aging. Chemicals act by disrupting the microtubules in the neurons through an increase in free radical generation.(1)

Microtubules play a significant role in brain plasticity and neurodegenerative diseases. Researchers suggest that microtubules may be an effective target for neurodegenerative diseases. (2) Microtubules form a structural scaffolding in a healthy brain and are essential for brain function.

Studies indicate that the impact of chemicals on microtubules in the neurons can be reduced, and microtubules stabilized, by pretreatment with sulforaphane.(1)

XGEVITY  (with Sulforaphane precursor Glucoraphanin)

REFERENCES:

(1) Pearson BL, et al. Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration. Nat. Commun. 2016 Mar 31;

(2) Penazzi L, et al. Microtubule Dynamics in Neuronal Development, Plasticity, and Neurodegeneration. Int Rev Cell Mol Biol. 2016

Sulforaphane - Inhibiting Glycation New Target for Alzheimer's Disease

Alzheimer's Disease (AD) and other neurodegenerative diseases, involve a complex etiology in both the initiation and progression of the disease. In AD known disease factors involve amyloid plaques, neurotangles (fibrils), inflammation and oxidative stress. Further research into this disease indicates that glycation of the amyloid, neurotangles and neurons may dramatically escalate destruction of the brain and accelerate disease progression. Mitigating glycation in the brain provides another target in the prevention of neurodegenerative diseases.

SULFORAPHANE targets the effects of oxidative stress and inflammation, both dominating factors in degenerative brain disease, including reduction of damage attributed to  the damaging glycation. Glycation of proteins, which occurs by the irreversible attachment of sugar to causes an accumulation of damaged brain proteins and is believed to be an important causative factor in AD.(1)

• Methylglyoxal (MG) - the role in Alzheimer's Disease. Glycated proteins lead to the formation of toxic Advanced Glycation Endproducts (AGEs) and are a significant source of inflammation. AGEs are found in high amounts in  the brains of Alzheimer's patients in conjunction with amyloid plaques and neurotangles.Methylglyoxal (MD) is a potent precursor of AGEs and is directly responsible for increased oxidative stress and deterioration of brain function.

• Sulforaphane increases cellular protection and enhances Methylglyoxal breakdown. Sulforaphane protects the brain by multiple paths.

1. Increases critical levels of intracellular glutathione -offering significant protection to the neurons including reduction of neuron death.
2. Increases breakdown of MG by elevating enzyme glyoxalase activity. 
3. Increases Brain Derived Neurotrophic Factor (BDNF). BDFN, which is neuro protective, and is reduced in AD patients. Lower BDNF levels are considered a biomarker for Alzheimer's.
4. Maintains critical glucose uptake for neuron energy. Methylglyoxal blocks important glucose uptake by the neurons which is  totally reversed by sulforaphane. When neurons are deprived of glucose (their main energy source) they can not survive.

•  Sulforaphane also is an inhibitory of neuroinflammation. Using human micro-glia like cells, sulforaphane has been shown to inhibit the proinflammatory cascade triggered by beta-amyloid peptides, thereby significantly reducing damaging inflammation occurring in the AD brain.(2)

XGEVITY (Glucoraphanin precursor to Sulforaphane)

REFERENCES:

(1) Angeloni C, et al. Antiglycative activity of sulforaphane: a new avenue to counteract neurodegeneration? Neural Regen Res. 2015 Nov.

(2) An YW, et al. Sulforaphane exerts its anti-inflammatory effect against amyloid-β peptide via STAT-1 dephosphorylation and activation of Nrf2/HO-1 cascade in human THP-1 macrophages. Neurobiol Aging 2016 Feb;

Brain & Neurodegenerative Diseases - The Central Role of Mitochondria

All aging starts at the cellular level including degeneration of the brain. Science has now identified dysfunction of the neuron mitochondria as the early central initiator in brain degeneration. When the neuronal mitochondria become dysfunctional, there is an inadequate supply of energy to the neuron, and subsequently the neuron dies. Early stages of neurodegenerative diseases have mitochondrial dysfunction common in their pathogenesis including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD) and amyotrophic lateral sclerosis (ALS). Indeed, the failure of cellular bioenergetics has been linked to neuron death and dementia.(1,2)

Research suggests that modulation and inhibition of mitochondrial dysfunction may increase neuron survival and provide a basis for extended brain longevity. As a cytoprotective agent, activation of transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2) protects the functioning of the mitochondria and is viewed as a target for possible prevention and treatment of neurodegenerative diseases associated with aging. Sulforaphane (and precursor Glucoraphanin) is one of the most powerful natural nrf2 activators, and may play a role in the intervention of age-related brain degeneration. (2) In addition, the natural extract andrographolide, carnosic acid and carnosol have been identified as a very strong nrf2 activators. (3, 4)

XGEVITY

AIR VITALITY

Both Contain the following nrf2 activators:

• Glucoraphanin / sulforaphane – from broccoli
• Andrographolide – from andrographis paniculata
• Carnosol & Carnosic Acid – from rosemary extract

REFERENCES:

(1) Grimm A, et al. Mitochondrial dysfunction: the missing link between aging and sporadic Alzheimer's disease. Biogerontology. 2015 Oct 14.
(2) Denzer I, et al. Modulation of mitochondrial dysfunction in neurodegenerative diseases via activation of nuclear factor erythroid-2-related factor 2 by food-derived compounds.
Pharmacol Res. 2015 Nov 25.
(3) Wu KC, et al. Screening of natural compounds as activators of the keap1-nrf2 pathway.
Planta Med. 2014
(4) de Oliveira MR. The Dietary Components Carnosic Acid and Carnosol as Neuroprotective Agents: a Mechanistic View. Mol Neurobiol. 2015 Nov 9

Powerful Yellows of Nature Support for Brain Aging

Brain aging is one of the inevitable signs of aging. Cognitive decline and dementia takes many forms, among the most common is Alzheimer's Disease (AD). AD is estimated to comprise 60-70% of all dementia cases worldwide. Similarly, the report from the

World Health Organization (WHO) states that "dementia is one of the major causes of disability and dependency among older people  worldwide." (1)  At this time, the only medicines available to treat AD only treat the symptoms and have no effect on the progression of the disease. In the near future, it is estimated that cases of AD will grow at an alarming rate, given the aging of the world's population.

Aging is the primary risk factor for Alzheimer's Disease. Neuronal cell death and synaptic degradation in Alzheimer's is attributed to gradual build-up of toxic mis-folded proteins (beta amyloid) and aggregation of tau protein fibrils and chronic brain inflammation. Each of these defective proteins kill neurons and synapses, rendering a degeneration of brain physical and mental function.

Yellows and golds in nature support brain health, and may reduce some of the factors associated with Alzheimer's Disease based upon animal research models. Research is strongly supportive of the role yellows can play in defusing brain inflammation, protecting against beta amyloid toxicity, tau fibril aggregation, microvascular circulation and provide protection of vital neurons and synapses.

RESEARCH - FACTORS INVOLVED IN BRAIN HEALTH

(1) Glycogen synthase kinase 3 (GSK3) - a kinase enzyme which has been implicated in many diseases including  Alzheimer's Disease, type 2 diabetes and cancer. In Alzheimer's Disease GSK3 has a key role in the accumulation of the toxic proteins. Inhibitors of GSK3 reduce beta amyloid and tau protein toxic buildup and are now a target of researchers.(2)

• Yellow natural GSK3 inhibitors include: curcumin, ginger, andrographolide, panax ginseng, apigenin, luteolin, quercetin, EGCG (Green Tea), hesperidin, rutin

(2) Beta Amyloid and Neurofibrillary (Tau) Tangles - Consensus of the scientific community is that beta amyloid, a toxic protein in the brain, is the initiator for further cascading events in the Alzheimer's progression. Beta amyloid accumulation then triggers a second protein toxin tau protein tangles (tau hyperphosphorylation).(3) Both proteins act as neurotoxins in the neurons and synapses. It appears that the over accumulation of Beta Amyloid stems from increased production and the inability to remove the excess.(4) This could involve a defect in the cellular ability to remove defective proteins (proteolysis including autophagy) (5) and / or an impairment of cerebral fluid removal system from the brain of the toxic proteins.

• Yellow natural Amyloid & Tau inhibitors include: curcumin, andrographolide, panax ginseng, scutellaria baicalensis (baicalin), schisandra, apigenin, luteolin, EGCG, carnsoic acid (rosemary), hesperidin, rutin, myricetin (bayberry), tetrahydrocurcumin
  

(3) Chronic Microglial Inflammation Over stimulation of the microglia in the brain is a primary cause of neuro inflammation. Microglia in brain become overly activated as a result of beta amyloid accumulation - theryby creating an inflammatory state in the brain, which further accelerates the destruction of brain neurons and synapses. (6)

Paradoxically, microglia may also play a protective role by clearing amyloid plaque via phagocytosis. Nrf2 activation in the microglia may support increase in phagocytosis activity, which has been demonstrated using sulforphane in test animals in brain hematoma clearance.(7) Sulforaphane also provides direct protection to brain from amyloid.(8)  Furthermore, studies indicate that taurine is able to reduce inflammation in the brain by switching the type of microglia from M1 (proinflammatory) to M2 (which promotes phagocytosis).(9) Taurine also acts directly on protein aggregates ameliorating toxicity.(10)

• Yellow natural Microglial inflammation inhibitors include: curcumin, andrographolide, apigenin, luteolin, carnosic acid (rosemary), schisandra, tetrahydrocurcumin
• Natural increase in microglia phagocytosis - Sulforaphane and taurine.

(4) Defective insulin Signaling (Type 2 diabetes). There is a strong association between type 2 diabetes and cognitive decline.(11, 12) Insulin resistance in the brain, associated with type 2 diabetes, is  correlated with Alzheimer's Disease.(12) Insulin resistance increases tau protein hyperphosphorylation (forming toxic tau protein tangles). EGCG (from Green Tea) has been shown to attenuate insulin resistance in the hippocampus area of the brain, thereby improving memory deficits related to Alzheimer's Disease. As part of the effect, EGCG inhibited glycogen synthase kinase-3β (GSK3), which plays a role in insulin resistance. Diet induced insulin resistance also has been shown to increase the manufacture of beta amyloid in the brain.(13)

• Yellow natural Reduction in Insulin Resistance. include: curcumin, andrographolide, panax ginseng, Scutellaria baicalensis (baicalin), carnosic acid, EGCG, alpha lipoic acid, tetrahydrocurcumin,

(5) Vascular Circulation (in brain) There is a strong correlation between neurovascular disorder and intensity of brain dysfunction in the progression of Alzheimer's Disease.(14) Decline in blood flow to the brain affects the neurons and their ability to function and survive. Areas of the brain which deficient blood flow show white areas in brain MRIs, referred to as "white matter lesions" and are common in the brains of Alzheimer's patients and are caused by affected blood flow to a region of the brain.(15) Patients with white matter lesions are associated with more rapid decreased cognition (16) and also contribute to occurrence of depression experienced in Alzheimer's patients.(17)

• Yellow natural Vascular Support. include: curcumin
• Vascular Support : include sulforaphane

(6) Iron and Brain Aging. While iron is a necessary mineral for good health, excessive accumulation in the brain is highly oxidative and inflammatory. Removal of excess iron from the brain, and iron homeostasis, will support healthy brain function and reduce potential for neurodegenerative diseases such as Alzheimers. Iron chelators, which remove excess cellular iron are effective in promoting brain health.(18)

• Yellow natural Iron Chelators. include: curcumin, ginger, luteolin, quercetin, myricetin, baicalin, EGCG (Green Tea)
• Other iron Chelators: Sulforaphane

KEY INGREDIENTS FOR SUPPORT OF BRAIN HEALTH

• Curcumin
• Luteolin
• Apigenin
• EGCG (Green Tea Extract)
• Myricetin (Bayberry Extract)
• Andrographolide
• Schisandra
• Ginger
• Panax Ginseng
• Quercetin
• Alpha Lipoic Acid
• Baicalin
• Hesperidin
• Rutin
• Icariin (Epimedium Extract)
• Carnosic Acid (Rosemary Extract)
• Tetrahydrocurcumin
• Sulforaphane (Glucoraphanin)
• Taurine

YELLOW LONGEVITY

YELLOW NATURALLY

LONGEVITY NATURALLY  (Yellows plus Taurine)

XGEVITY (Yellows plus Sulforaphane)

REFERENCES:

(1) World Health Organization (WHO). Dementia. March 2015.

(2) Maqbool M, et al. Pivotal role of glycogen synthase kinase-3: A therapeutic target for Alzheimer's disease. Eur J Med Chem. 2015 Oct 21

(3) Musiek ES, et al. Three dimensions of the amyloid hypothesis: time, space and 'wingmen'.  Nat Neurosci. 2015 Jun

(4) Gallina P, et al. Aβ Clearance, “hub” of Multiple Deficiencies Leading to Alzheimer Disease. Front Aging Neurosci. 2015;

(5) Salminen A, et al. Impaired autophagy and APP processing in Alzheimer's disease: The potential role of Beclin 1 interactome. Prog Neurobiol. 2013 Jul-Aug.

(6) Wang WY, et al. Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. Ann Transl Med. 2015 Jun

(7) Zhao X, et al. Cleaning up after ICH: the role of Nrf2 in modulating microglia function and hematoma clearance.  J Neurochem 2015 Apr

(8) Zhang R, et al. Sulforaphane ameliorates neurobehavioral deficits and protects the brain from amyloid β deposits and peroxidation in mice with Alzheimer-like lesions. Am J Alzheimers Dis Other Demen. 2015 Mar.

(9) Ward RJ, et al. Ageing, neuroinflammation and neurodegeneration. Front Biosci (Schol Ed) 2015 Jun

(10) Chaturvedi SK, et al. Biophysical insight into the anti-amyloidogenic behavior of taurine. Int J Biol Macromol. 2015 Sep

(11) Li M, et al. Fasting and systemic insulin signaling regulate phosphorylation of brain proteins that modulate cell morphology and link to neurological disorders. J Biol Chem. 2015 Oct 23

(12) Sato N, et al. The roles of lipid and glucose metabolism in modulation of β-amyloid, tau, and neurodegeneration in the pathogenesis of Alzheimer disease. Front Aging Neurosci 2015 Oct

(13) Ho L, et al. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. FASEB J. 2004 May

(14) Pachalska M, et al. Vascular Factors and Cognitive Dysfunction in Alzheimer Disease. Med Sci Monit. 2015 Nov

(15) Alzheimer's Society. 2015.

(16)  Hanaoka T, et al.  Relationship between white matter lesions and regional cerebral blood flow changes during longitudinal follow up in Alzheimer's disease. Geriatr Ferontol Int 2015 Aug 5.

(17) Lee JJ, et al. Impact of White Matter Lesions on Depression in the Patients with Alzheimer's Disease. Psychiatry Investig 2015 Oct

(18) Ward RJ, et al. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 2014 Oct

ALZHEIMERS INGREDIENTS RESEARCH:

(19) Tapia-Rojas C, et al.  Andrographolide activates the canonical Wnt signalling pathway by a mechanism that implicates the non-ATP competitive inhibition of GSK-3β: autoregulation of GSK-3β in vivo. Biochem J. 2015 Mar 1

(20) Wang C, et al. Downregulation of PI3K/Akt/mTOR signaling pathway in curcumin-induced autophagy in APP/PS1 double transgenic mice. Eur J Pharmacol. 2014 Oct 

(21) Venigalla M, et al. Novel promising therapeutics against chronic neuroinflammation and neurodegeneration in Alzheimer's disease. Neurochem Int. 2015 Oct 31

(22) Venigalla M, et al. Curcumin and Apigenin - novel and promising therapeutics against chronic neuroinflammation in Alzheimer's disease. Neural Regen Res. 2015 Aug;

(23) Jia N, et al. (-)-Epigallocatechin-3-gallate alleviates spatial memory impairment in APP/PS1 mice by restoring IRS-1 signaling defects in the hippocampus. Mol Cell Biochem. 2013 Aug

(24) de Oliverira. The Dietary Components Carnosic Acid and Carnosol as Neuroprotective Agents: a Mechanistic View. Mol Neurobiol. 2015 Nov 9

(25) Rasoolijazi H, et al. The protective role of carnosic acid against beta-amyloid toxicity in rats. Scientific WorldJournal 2013 Oct 24

(26) Azad N, et al. Neuroprotective effects of carnosic Acid in an experimental model of Alzheimer's disease in rats. Cell J. 2011 Spring.

(27) Shi X, et al. Curcumin inhibits Aβ-induced microglial inflammatory responses in vitro: Involvement of ERK1/2 and p38 signaling pathways. Neurosci Lett. 2015 May

(28) Rezai-Zadeh K, et al. Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression. J Neuroinflammation. 2008 Sep 25

(29) Park SY, et al. α-Iso-cubebene exerts neuroprotective effects in amyloid beta stimulated microglia activation.  Neurosci Lett. 2013 Oct 25

(30) Bustanji Y, et al. Inhibition of glycogen synthase kinase by curcumin: Investigation by simulated molecular docking and subsequent in vitro/in vivo evaluation. J Enzyme Inhib Med Chem. 2009 Jun.

(31) Mathew M, et al. In vitro evaluation of anti-Alzheimer effects of dry ginger (Zingiber officinale Roscoe) extract.

(32) Dong HJ, et al. Curcumin attenuates ischemia-like injury induced IL-1β elevation in brain microvascular endothelial cells via inhibiting MAPK pathways and nuclear factor-κB activation. Neuro Sci. 2014 Sep

(33) Mann GE. Nrf2-mediated redox signalling in vascular health and disease. Free Radic Biol Med. 2014 Oct.

(34) Baum L, et al. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal models. J Alzheimers Dis. 2004 Aug

(35) Oboh G, et al. Antioxidant and inhibitory effect of red ginger (Zingiber officinale var. Rubra) and white ginger (Zingiber officinale Roscoe) on Fe(2+) induced lipid peroxidation in rat brain in vitro. Exp Toxicol Pathol. 2012 Jan

(36) Hofer T, et al. Comparison of food antioxidants and iron chelators in two cellular free radical assays: strong protection by luteolin. J Agric Food Chem. 2014 Aug 20

(37) Mladěnka P, et al. In vitro analysis of iron chelating activity of flavonoids. J Inorg Biochem. 2011 May

(38) Mandel SA, et al. Cell signaling pathways and iron chelation in the neurorestorative activity of green tea polyphenols: special reference to epigallocatechin gallate (EGCG). J Alzheimers Dis. 2008 Oct

(39) Lavich IC, et al. Sulforaphane rescues memory dysfunction and synaptic and mitochondrial alterations induced by brain iron accumulation. Neuroscience. 2015 Aug 20.