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APP x TAU	1

The accumulation of the amyloid-β (Aβ) peptide in the form of insoluble fibrillar deposits and soluble oligomeric aggregates is widely believed to play a causal role in Alzheimer's disease (AD). Proteolytic cleavage of APP by the β-site APP cleaving enzyme (BACE1) near the C-terminus results in the formation of the APP C-terminal fragment (CTF) C99, a substrate for subsequent cleavage by γ-secretase to generate Aβ. Alternatively, APP cleavage by α-secretase to generate the APP CTF C83 occurs within the Aβ region, precluding its formation. Therefore, modulation of β- and/or γ-secretase activity represents important therapeutic targets. Transgenic mice overexpressing human APP generate detectable levels of APP CTFs and Aβ. We have shown that highly sensitive and specific methods for determining levels of APP CTFs and Aβ are useful for understanding how genetic manipulation of APP processing impacts Aβ generation and accumulation.

Highly sulfated glycosaminoglycans in the pathogenesis of Alzheimer′s disease.

Author: Castillo, Gerardo M. ; Cummings, Joel A. ; Choi, Paula ; Snow, Alan D.

Heparan sulfate proteoglycans (HSPGs) and their containing glycosaminoglycans (GAGs) are postulated to play primary roles in the pathogenesis of Alzheimer′s disease (AD) by contributing to the formation, deposition, and persistence of beta-amyloid protein (Aβ)-containing deposits in brain.Heparan sulfate GAGs are also specifically immunolocalized to the characteristic lesions in AD including neuritic plaques, cerebrovascular amyloid deposits and neurofibrillary tangles.Our previous studies have demonstrated that HSPGs not only bind Aβ 1-40 and 1-42 with high affinity, but are also effective enhancers of Aβ 1-40 fibril formation and cause Aβ 1-42 fibril stability.These effects occur in a dose-dependent manner.Removal of specific sulfates from heparin GAGs (i.e. O-sulfate or N-sulfate) leads to a general decrease in enhancement of Aβ fibril formation, whereas complete removal of all sulfates from heparin (i.e. completely desulfated N-acetylated heparin) results in a complete loss of Aβ fibril enhancement.These latter studies indicate that the sulfate moieties of heparin/ heparan sulfate GAGs are critically involved in the enhancement of Aβ fibrillogenesis.Previous studies indicate that heparan sulfate GAGs also play an important role in neurofibrillary tangle induction by contributing to the formation of paired helical filaments.New studies by our group now indicate that under specific exptl. conditions, highly sulfated GAGs and related macromols. spontaneously induce amyloid plaque formation in vitro that is virtually identical to compact amyloid plaques present in human AD brain.In addition, we are utilizing pre-formed amyloid plaques in vitro for the development of new rodent models to rapidly determine the efficacy of potential Aβ/amyloid plaque inhibitors.The discovery that highly sulfated GAGs can induce amyloid plaque core formation, in addition to paired helical filament formation, further demonstrates the critical importance of highly sulfated proteoglycans/GAGs in the pathogenesis of AD.Supported by NIH and ProteoTech Inc.

Scientific ReportsQ3 · CROSS-FIELD

The Amazon rain forest plant Uncaria tomentosa (cat’s claw) and its specific proanthocyanidin constituents are potent inhibitors and reducers of both brain plaques and tangles

Q3 · CROSS-FIELD

ArticleOA

Author: Cummings, Joel A ; Snow, Alan D ; Rockenstein, Edward ; Lake, Thomas ; Masliah, Eliezer ; Choi, Paula Y ; Cam, Judy ; Larsen, Lesley ; Tanzi, Rudolph E ; Hu, Qubai ; Nguyen, Beth P ; Castillo, Gerardo M ; Kirschner, Daniel A ; Pan, Weihong ; Wood, Steven G ; Kastin, Abba J ; Lorimer, Stephen

AbstractBrain aging and Alzheimer’s disease both demonstrate the accumulation of beta-amyloid protein containing “plaques” and tau protein containing “tangles” that contribute to accelerated memory loss and cognitive decline. In the present investigation we identified a specific plant extract and its constituents as a potential alternative natural solution for preventing and reducing both brain “plaques and tangles”. PTI-00703 cat’s claw (Uncaria tomentosa from a specific Peruvian source), a specific and natural plant extract from the Amazon rain forest, was identified as a potent inhibitor and reducer of both beta-amyloid fibrils (the main component of “plaques”) and tau protein paired helical filaments/fibrils (the main component of “tangles”). PTI-00703 cat’s claw demonstrated both the ability to prevent formation/aggregation and disaggregate preformed Aβ fibrils (1–42 and 1–40) and tau protein tangles/filaments. The disaggregation/dissolution of Aβ fibrils occurred nearly instantly when PTI-00703 cat’s claw and Aβ fibrils were mixed together as shown by a variety of methods including Thioflavin T fluorometry, Congo red staining, Thioflavin S fluorescence and electron microscopy. Sophisticated structural elucidation studies identified the major fractions and specific constituents within PTI-00703 cat’s claw responsible for both the observed “plaque” and “tangle” inhibitory and reducing activity. Specific proanthocyanidins (i.e. epicatechin dimers and variants thereof) are newly identified polyphenolic components within Uncaria tomentosa that possess both “plaque and tangle” reducing and inhibitory activity. One major identified specific polyphenol within PTI-00703 cat’s claw was epicatechin-4β-8-epicatechin (i.e. an epicatechin dimer known as proanthocyanidin B2) that markedly reduced brain plaque load and improved short-term memory in younger and older APP “plaque-producing” (TASD-41) transgenic mice (bearing London and Swedish mutations). Proanthocyanidin B2 was also a potent inhibitor of brain inflammation as shown by reduction in astrocytosis and gliosis in TASD-41 transgenic mice. Blood-brain-barrier studies in Sprague-Dawley rats and CD-1 mice indicated that the major components of PTI-00703 cat’s claw crossed the blood-brain-barrier and entered the brain parenchyma within 2 minutes of being in the blood. The discovery of a natural plant extract from the Amazon rain forest plant (i.e. Uncaria tomentosa or cat’s claw) as both a potent “plaque and tangle” inhibitor and disaggregator is postulated to represent a potential breakthrough for the natural treatment of both normal brain aging and Alzheimer’s disease.

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Pipeline

Pipeline Snapshot as of 20 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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