Amyloid-Precursor-Protein-Lowering Small Molecules for Disease Modifying Therapy of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the most common form of dementia in the elderly with progressive cognitive decline and memory loss. According to the amyloid-hypothesis, AD is caused by generation and subsequent cerebral deposition of β-amyloid (Aβ). Aβ is generated through sequential cleavage of the transmembrane Amyloid-Precursor-Protein (APP) by two endoproteinases termed beta- and gamma-secretase. Increased APP-expression caused by APP gene dosage effects is a risk factor for the development of AD. Here we carried out a large scale screen for novel compounds aimed at decreasing APP-expression. For this we developed a screening system employing a cell culture model of AD. A total of 10,000 substances selected for their ability of drug-likeness and chemical diversity were tested for their potential to decrease APP-expression resulting in reduced Aβ-levels. Positive compounds were further evaluated for their effect at lower concentrations, absence of cytotoxicity and specificity. The six most promising compounds were characterized and structure function relationships were established. The novel compounds presented here provide valuable information for the development of causal therapies for AD.

Beneficial Effects of the β-Secretase Inhibitor GRL-8234 in 5XFAD Alzheimer’s Transgenic Mice Lessen During Disease Progression

“…In recent clinical trial failure of β-secretase inhibitor, it is pointed out that the observed liver toxicity may not necessarily be due to “off-target” (i.e., “off-BACE1) side effects but reflect “off-site” effects (i.e., BACE1 inhibition on β-galactoside α-2,6-sialyltransferase I in liver) that could be masked in animal models [53]. Our results suggest that a combination of the BACE1 inhibitor and agents that block BACE1-elevating pathways [30, 54, 55], lower APP expression [56, 57] or remove Aβ plaques (e.g., passive immunization) [58] may provide a more efficacious and safe strategy to treat memory deficits in AD with established amyloid pathology.…”

Effects of BACE1 haploinsufficiency on APP processing and Aβ concentrations in male and female 5XFAD Alzheimer mice at different disease stages

“…Consequently, BACE1 +/− ·5XFAD mice and GRL8234-treated 5XFAD mice at ≥12 months of age have high residual levels of toxic Aβ oligomers and C99 (even if partially reduced), which render these mice no longer responsive to cognitive rescue by partial BACE1 inhibition. To avoid potential mechanism-based adverse effects that may be caused by direct over-suppression of β-secretase activities such as chronic exposure to a highest dose of inhibitor drugs (Filser et al, 2015), our results suggest that BACE1 inhibitors in combination with APP-lowering drugs (Rosenkranz et al, 2013, Asuni et al, 2014) or agents that can block disease-specific BACE1-elevating mechanisms (Medeiros et al, 2012, Ly et al, 2013, Devi and Ohno, 2014) may represent safer and more efficacious interventions to treat memory deficits in diagnosed AD with established amyloid pathology.…”

Protein Misfolding in Prion and Prion-Like Diseases: Reconsidering a Required Role for Protein Loss-of-Function

“…The prevailing toxic gainof-function hypothesis in the field is the Amyloid Cascade Hypothesis, which proposes that A␤ has an early role in disease and induces tau pathology [74]. Thus A␤PP, A␤ peptides and tau have been proposed as targets for AD drug development [75][76][77]. It is important to consider how loss of the normal roles of these proteins may impact disease progression so that appropriate therapeutic interventions can be developed.…”