Therapeutic leads from microorganisms, fungi and plants in medical research: treatment discoveries for alzheimer's disease

Lee, Robert K. (2001) Therapeutic leads from microorganisms, fungi and plants in medical research: treatment discoveries for alzheimer's disease. [Proceedings Paper]

Alzheimer’s disease (AD) is characterized by personality and mental dysfunctions, as well as drastic intellectual and occupational impairments. There are no drugs to cure or prevent AD. The healthcare costs associated with the 4 million Americans with AD amounted to $100 billion in 1998. There are currently 20 million cases of AD worldwide. As the geriatric population worldwide continues to grow, AD will become a social and medical problem of escalating proportions. One of the characteristic hallmarks of AD brains is the abnormal accumulation of amyloid plaques. These plaques are composed aggregates of b-amyloid (Aß) peptides that are derived from the much larger amyloid precursor protein, APP. Cultured neuronal cells that are genetically modified to overexpress multiple copies of the APP gene produce abundant amounts of amyloid and are susceptible to neurodegeneration. Overexpression of the APP gene in transgenic mice also produces some of the pathologic symptoms of AD, including memory impairment, accumulation of amyloid plaques and brain degeneration. These studies show that overproduction of APP or Aß can induce some of the pathologies of AD. My colleagues and I recently discovered a novel biochemical mechanism that activates the APP gene in brain cells, and have used this discovery to identify novel drug candidates. Our in vitro studies demonstrate that prostaglandin E₂ (PGE₂ stimulates APP synthesis (both messenger RNA and holoprotein) in a class of brain cells called astrocytes. PGE₂ is a product of inflammation, and is formed by the cyclooxygenation of arachidonic acid liberated from membrane phospholipids by phospholipase A₂ (PL₂. ). Postmortem analysis of AD brains confirmed that the levels of both PLA₂ and cyclooxygenase-2 (COX-2) enzymes were elevated. The stimulatory effect of PGE₂ on APP synthesis in cultured brain astrocytes is mediated by G-proteins that are linked to elevations in cyclic adenosine monophosphate (cAMP, an intracellular signal). To verify that cAMP is a critical signal for APP gene activation, we demonstrated that forskolin (derived from the roots of the Indian plant Coleus forskohlii), which directly activates adenylate Cyclase to elevate cAMP also stimulated APP overexpession in cultured astmcytes. Cyclospmin A and tacrolimus (also known as FK-506) isolated from fungi Tolypocladium inflatum) and soil microorganisms (Streptomyces polysporum) respectively, effectively inhibited APP overexpession in brain astrocytes treated with PGE₂. Cyclosporin A and tacrolimus exert their inhibitory effects by binding to immunophilin receptors. Therefore, we have initiated efforts to identify other immunophilin drugs (synthetic analogs or other natural-derived compounds) that might also be effective in inhibiting APP overexpression. Our search for AD therapeutics has also identified plant-derived drugs that accelerate the breakdown of APP to form non-amyloidogenic APP fragments. Resveratrol is an extract from gapes and the roots of a Peruvian tree (Cassia quinquangulata); it reduces COX-2, inhibits arachidonic acid release and suppesses PGE₂ synthesis. We found that resveratrol accelerates APP breakdown to form non-amyloidogenic derivatives in cultured brain astrocytes or in cultured brain neurons. Tetrahydrocannabinol, the principal psychoactive ingredient in marijuana (Cannabis sativa), activates cannabinoid receptors that inhibit cAMP formation. We discovered that synthetic and natural cannabinoids also suppress astrocytic APP overexpression caused by PGE₂ These findings demonstrate that the discovery of biochemical mechanisms underlying disease provide important targets for drug action, and that drugs derived from natural products can provide useful therapeutic leads for treating diseases.

Full text available from:

Abstract

Alzheimer’s disease (AD) is characterized by personality and mental dysfunctions, as well as drastic intellectual and occupational impairments. There are no drugs to cure or prevent AD. The healthcare costs associated with the 4 million Americans with AD amounted to $100 billion in 1998. There are currently 20 million cases of AD worldwide. As the geriatric population worldwide continues to grow, AD will become a social and medical problem of escalating proportions. One of the characteristic hallmarks of AD brains is the abnormal accumulation of amyloid plaques. These plaques are composed aggregates of b-amyloid (Aß) peptides that are derived from the much larger amyloid precursor protein, APP. Cultured neuronal cells that are genetically modified to overexpress multiple copies of the APP gene produce abundant amounts of amyloid and are susceptible to neurodegeneration. Overexpression of the APP gene in transgenic mice also produces some of the pathologic symptoms of AD, including memory impairment, accumulation of amyloid plaques and brain degeneration. These studies show that overproduction of APP or Aß can induce some of the pathologies of AD. My colleagues and I recently discovered a novel biochemical mechanism that activates the APP gene in brain cells, and have used this discovery to identify novel drug candidates. Our in vitro studies demonstrate that prostaglandin E₂ (PGE₂ stimulates APP synthesis (both messenger RNA and holoprotein) in a class of brain cells called astrocytes. PGE₂ is a product of inflammation, and is formed by the cyclooxygenation of arachidonic acid liberated from membrane phospholipids by phospholipase A₂ (PL₂. ). Postmortem analysis of AD brains confirmed that the levels of both PLA₂ and cyclooxygenase-2 (COX-2) enzymes were elevated. The stimulatory effect of PGE₂ on APP synthesis in cultured brain astrocytes is mediated by G-proteins that are linked to elevations in cyclic adenosine monophosphate (cAMP, an intracellular signal). To verify that cAMP is a critical signal for APP gene activation, we demonstrated that forskolin (derived from the roots of the Indian plant Coleus forskohlii), which directly activates adenylate Cyclase to elevate cAMP also stimulated APP overexpession in cultured astmcytes. Cyclospmin A and tacrolimus (also known as FK-506) isolated from fungi Tolypocladium inflatum) and soil microorganisms (Streptomyces polysporum) respectively, effectively inhibited APP overexpession in brain astrocytes treated with PGE₂. Cyclosporin A and tacrolimus exert their inhibitory effects by binding to immunophilin receptors. Therefore, we have initiated efforts to identify other immunophilin drugs (synthetic analogs or other natural-derived compounds) that might also be effective in inhibiting APP overexpression. Our search for AD therapeutics has also identified plant-derived drugs that accelerate the breakdown of APP to form non-amyloidogenic APP fragments. Resveratrol is an extract from gapes and the roots of a Peruvian tree (Cassia quinquangulata); it reduces COX-2, inhibits arachidonic acid release and suppesses PGE₂ synthesis. We found that resveratrol accelerates APP breakdown to form non-amyloidogenic derivatives in cultured brain astrocytes or in cultured brain neurons. Tetrahydrocannabinol, the principal psychoactive ingredient in marijuana (Cannabis sativa), activates cannabinoid receptors that inhibit cAMP formation. We discovered that synthetic and natural cannabinoids also suppress astrocytic APP overexpression caused by PGE₂ These findings demonstrate that the discovery of biochemical mechanisms underlying disease provide important targets for drug action, and that drugs derived from natural products can provide useful therapeutic leads for treating diseases.

[error in script]

Item Type:	Proceedings Paper
Additional Information:	Available at Perpustakaan Sultan Abdul Samad, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia. QH75 A1I61 2000 Call Number
AGROVOC Term:	medicinal plants
AGROVOC Term:	microorganisms
AGROVOC Term:	therapeutic diets
AGROVOC Term:	experimentation
AGROVOC Term:	research
AGROVOC Term:	biotechnology
AGROVOC Term:	pharmaceutical industry
AGROVOC Term:	diseases
AGROVOC Term:	innovation
Geographical Term:	United States
Depositing User:	Nor Hasnita Abdul Samat
Date Deposited:	21 Jul 2025 08:50
Last Modified:	21 Jul 2025 08:50
URI:	http://webagris.upm.edu.my/id/eprint/693

Actions (login required)

View Item