Natural Substances That Modulate Amyloid-Beta Precursor Protein Which Subsequently Reduces Amyloid Beta


Amyloid beta, the principal component of senile plaques, is thought to be the pathogenesis of Alzheimer’s disease.  The development of Alzheimer’s disease is associated with plaques and tangles in the brain.  These plaques and tangles are referred to as amyloids which are aggregates of proteins that become folded into a shape that allows many copies of that protein to stick together.  The amyloid-cascade hypothesis states that the production and excessive accumulation of amyloid beta is the primary pathological event leading to Alzheimer’s disease.  1 

The precursor to amyloid beta is Amyloid Precursor Protein (APP), which is endogenous in brain cells and is inert.  The inert APP is converted by proteolytic enzymes by being cleaved by proteases in the secretase family, namely:  2

Alpha secretase

Alpha secretase is considered to be part of the non-amyloidogenic pathway in APP processing since its cleavage precludes amyloid beta formation.  The alpha secretase event precludes the generation of amyloid beta.

Thus a therapeutic strategy for Alzheimer’s disease is to elevate the non-amyloidogenic pathway by stimulation of alpha secretase activity.

There are certain natural substances that stimulate the activity of alpha secretase.

Beta secretase (or BACE1)

The initial stage of cleaving APP is done by beta secretase.  Thus a therapeutic strategy for Alzheimer’s disease is to inhibit beta secretase. 

There are certain natural substances that inhibit the activity of beta secretase.

Gamma secretase

APP is further cleaved by gamma secretase after beta-secretase cleavage generates the amyloid beta fragment.  The inhibition of gamma secretase activity has been considered a strategy in the treatment of Alzheimer’s disease.

No direct inhibitor of gamma secretase as a single active compound extracted from natural substances has been reported.  3

However, there are a few natural substances that have since been identified as inhibitors of gamma secretase.

Excessive accumulation of amyloid beta can cause neurotoxic effects in the brain.  Proactive efforts to minimize amyloid beta toxicity in the brain is necessary as an overall healthy neurological strategy.

The Tabs below lists the three secretases and the natural substances that either stimulate or inhibit for each.

Modulators of Amyloid-Beta Precursor Protein

Alpha-secretase Stimulators

Epigallocatechin-3-gallate (EGCG)Green teaAs a validation of these findings in vivo, we treated Tg APPsw transgenic mice overproducing Abeta with EGCG and found decreased Abeta levels and plaques associated with promotion of the nonamyloidogenic alpha-secretase proteolytic pathway. These data raise the possibility that EGCG dietary supplementation may provide effective prophylaxis for AD.11
In summary, ADAM10 activation is necessary for EGCG promotion of non-amyloidogenic (alpha-secretase cleavage) APP processing. Thus, ADAM10 represents an important pharmacotherapeutic target for the treatment of cerebral amyloidosis in Alzheimer disease.2
ResveratrolRed Wine/Red grape skins/Japanes knottweedNevertheless, resveratrol diminished plaque formation in a region specific manner. The largest reductions in the percent area occupied by plaques were observed in medial cortex (-48%), striatum (-89%) and hypothalamus (-90%). The changes occurred without detectable activation of SIRT-1 or alterations in APP processing. 3
Cryptotanshinone (CTS)Radix Salvia miltiorrhiza (DanShen)Results showed that Cryptotanshinone (CTS) treatment of cortical neurons overexpressing Swedish mutant human APP695 markedly elevated ADAM10 protein, and the inhibitor of ADAM10 inhibited the CTS-induced increase in alpha-secretase activity, suggesting CTS modulated alpha-secretase activity by upregulation ADAM10 protein. By using several specific protein kinase inhibitors, we showed that phosphatidylinositol 3-kinase (PI3K) mediated the CTS-induced alpha-secretase activation.4
Acetyl-L-Carnitine (ALC) Acetyl-L-Carnitine (ALC)Our findings suggest that the benefits of acetyl-L-carnitine (ALC) reported in previous clinical studies are underscored by the specific biological mechanism of this compound on APP metabolism. In fact, ALC can directly influence the primary event in Alzheimer's disease pathogenesis, i.e. the Amyloid beta cascade, promoting alpha-secretase activity and directly affecting the release of the non amyloidogenic metabolite.5
MagnesiumMagnesium Glycinate/Manesium ThreonateNormal AbetaPP processing could be restored when magnesium was adjusted back to physiological concentration. These data demonstrate that AbetaPP processing can be modulated by magnesium and at high [Mg2+]o, AbetaPP processing favors the alpha-secretase cleavage pathway. Our findings suggest that supplementation of magnesium has a therapeutic potential for preventing AD.6
Huperzia serrataChinese club moss or Huperzine AHup A-induced alphaAPPs release was significantly reduced by the protein kinase C (PKC) inhibitors GF109203X and Calphostin C. These data, together with the finding that the PKCalpha level was enhanced prior to the increase of alphaAPPs secretion, indicate that PKC may be involved in Hup A-induced alphaAPPs secretion by HEK293 APPsw cells. Our data suggest alternative pharmacological mechanisms of Hup A relevant to the treatment of Alzheimer's disease.7
Apium graveolens LinnChinese celery, Wild celery or celery seedsL-3-n-butylphthalide (L-NBP) treatment significantly improved learning deficits, as well as long-term spatial memory, compared with vehicle control treatment. L-NBP treatment significantly reduced total cerebral Abeta plaque deposition and lowered Abeta levels in brain homogenates but had no effect on fibrillar Abeta plaques, suggesting preferential removal of diffuse Abeta deposits. Furthermore, we found that L-NBP markedly enhanced soluble amyloid precursor protein secretion (alphaAPPs), alpha-secretase, and PKCalpha expression but had no effect on steady-state full-length APP. 8

Beta-secretase 1 (BACE1) Inhibitors

NeferineNelumbo nucifera (also known as Indian lotus, sacred lotus, bean of India, or simply lotus)The results demonstrate that the anti-amnesic effect of neferine may be mediated via antioxidant and anti-inflammatory capacities, as well as inhibition of ChEs and BACE1.1
Ginsenoside Rg1Panax notoginseng (American and Korean ginseng)The results showed that Ginsenoside Rg1 (1) could inhibit beta-secretase activity in vitro and also protect the PC12 cells against injuries caused by exposure of PC12 cells to 50 microM Abeta(25-35) for 48 h. The cell death, LDH release, NO release, ROS production, lipid peroxidation, intracellular calcium elevation, and apoptosis are associated events induced by Abeta that can be rescued by 1 in PC12 cells. In conclusion, 1 may be a promising agent for AD, and the mechanism is related to beta-secretase inhibition and protection against Abeta-induced cytotoxicity.2
HispidinPhellinus linteus (is a medicinal mushroom; also known as Japanese "meshimakobu", Chinese "song gen", Korean "sanghwang", English "Meshima", American English "black hoof mushroom") In the course of screening for anti-dementia agents from natural products, a beta-secretase (BACE1) inhibitor was isolated from the culture broth of Phellinus linteus and identified as hispidin. 3
DHEADHEAIn the present paper we show that pretreatment with DHEA is able to rescue the increase of mRNA expression, protein levels, and activity of BACE, produced by oxidative stress in NT2 neurons. BACE, being the enzyme that initiates the production of Abeta, is a drug target for AD. Our results imply that DHEA administration may slow down the AD pathological process, lowering Abeta accumulation.4
Epigallocatechin-3-gallate (EGCG)Green teaIn the course of searching for BACE1 (beta-secretase) inhibitors from natural products, the ethyl acetate soluble fraction of green tea, which was suspected to be rich in catechin content, showed potent inhibitory activity. (-)-Epigallocatechin gallate, (-)-epicatechin gallate, and (-)-gallocatechin gallate were isolated with IC(50) values of 1.6 x 10(-6), 4.5 x 10(-6), and 1.8 x 10(-6) M, respectively. 5
Green tea at a final assay concentration of 0.03 mg/mL inhibited beta-secretase by 38%. These novel findings suggest that tea infusions contain biologically active principles, perhaps acting synergistically, that may be used to retard the progression of the disease assuming that these principles, yet to be identified, reach the brain.6
Heparan sulfateAortic Glycosaminoglycans Bovine CartilageCleavage of amyloid precursor protein (APP) by the Alzheimer's beta-secretase (BACE1) is a key step in generating amyloid beta-peptide, the main component of amyloid plaques. Here we report evidence that heparan sulfate (HS) interacts with beta-site APP-cleaving enzyme (BACE) 1 and regulates its cleavage of APP. We show that HS and heparin interact directly with BACE1 and inhibit in vitro processing of peptide and APP substrates.7
2,2’,4’-trihydroxychalcone (TDC)Glycyrrhiza glabra (Licorice root)Here, we reported that the natural product 2,2',4'-trihydroxychalcone (TDC) from Glycyrrhiza glabra functioned as a specific non-competitive inhibitor against BACE1 enzyme, and potently repressed beta-cleavage of APP and production of Abeta in human embryo kidney cells-APPswe cells.8

Gamma-Secretase Inhibitors

Pterocarpus erinaceusPterocarpus erinaceus We also showed that the Pterocarpus erinaceus extract significantly decreased Aβ production, displaying effects similar to those of DAPT (γ-secretase inhibitor) on APP processing, but may act on another inhibition site.1
Cimicifuga racemosaCimicifuga racemosa (Black Cohosh)The invention features methods of reducing the level of a β-amyloid (Aβ) polypeptide using an Cimicifuga extract. The invention also features methods of producing an active fraction from an extract of Cimicifuga. The invention further features a composition containing an active fraction of a Cimicifuga extract and an article of manufacture containing such a composition.2

Plaque Formation in the Alzheimer's Brain

Cover Photo:  Sacred Lotus Flower