Natural product extracts that reduce accumulation of the alzheimer’s amyloid β peptide

Abstract

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Without a treatment that significantly delays the progression of the disease over 14 million Americans are likely to be affected with AD by the middle of the 21st Century, presenting an enormous economic and social burden. Evidence gathered over the last two decades has implicated the abnormal accumulation of A beta, in particular the longer more amyloidogenic form A beta42, as a potential causative agent in the disease. To screen for compounds that reduce A beta accumulation we have established several high throughput, cell based screens capable of the sensitive and selective detection of A beta40 and A beta42. Using these screens we have analyzed a proprietary library of natural product extracts for their ability to influence A beta accumulation. Using this approach, we have identified several agents capable of influencing total A beta concentration. In addition, we have identified one extract that selectively reduces A beta42. Intracerebroventricular administration of this agent to mice results in a selective reduction in A beta42 in the brain.

Molecular Characterization of Mutations That Cause Globoid Cell Leukodystrophy and Pharmacological Rescue Using Small Molecule Chemical Chaperones

“…Protein standards were purchased from New England Biolabs (Ipswich, MA). We performed SDS-PAGE, protein transblotting, and antibody staining using standard methodology (Yager et al, 2002). We used the following antibodies: affinity-purified anti-GALC rabbit polyclonal antibody (CL1475) at 1:1000 (Lee et al, 2005); affinity-purified anti-GALC chicken polyclonal antibody (CL1021AP) at 1:1000; anti-V5 epitope tag antibody at 1:1000 (Abcam, Cambridge, MA).…”

Role of the APP Non-Amyloidogenic Signaling Pathway and Targeting α-Secretase as an Alternative Drug Target for Treatment of Alzheimers Disease

“…An approach to identify agents capable of reducing total A concentration successfully led to a natural extract compound that upon intracerebroventricular administration in mice resulted in a selective reduction of A in the brain [273]. Since neurotrophin receptors are expressed in AD, small molecule libraries are being screened to identify non-peptide neurotrophin agonist or antagonist activity [274].…”

“…Thus, a proprietary library of natural product extracts was screened (cellbased) for their ability to influence A accumulation. Using this approach, several agents capable of influencing total A concentration were identified with an extract that upon intracerebroventricular administration selectively reduced A 42 in the mice brains [273]. (Fig.…”

Natural Product and Natural Product-Derived Gamma Secretase Modulators from Actaea Racemosa Extracts

“…In follow-up to this initial report, a subsequent unbiased screening study was undertaken with the goal of identifying an already approved drug or a nutritional supplement with GSM activity [11]. Among a total sample set of approximately 2000 individual compounds and mixtures of compounds, including previously identified GSMs, a single sample was identified with robust and potent selective Aβ42 lowering activity well below a concentration that resulted in any cellular toxicity [12]. This one sample was a standard alcoholic extract of the root and rhizome of Actaea racemosa , the black cohosh plant.…”