Novel tricyclic pyrone compounds prevent intracellular APP C99-induced cell death

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the progressive and global loss of cognitive functions. Pathological features include a loss of neurons in vulnerable brain regions and the extracellular deposition of abnormal protein aggregates known as amyloid plaques. Amyloid-beta protein (A beta is the major component of amyloid plaques and is derived from a larger transmembrane glycoprotein, termed amyloid beta protein precursor (APP), by proteolysis. The AD research has focused on A beta production and metabolism, its extracellular deposition, and its cellular toxicity. Recent evidence, however, suggests that A beta as well as the C-terminal fragments (CTF) of APP can accumulate intraneuronally. The neuronal loss and synaptic transmission deficit in AD may therefore depend on intraneuronal accumulation of A beta/CTF rather than on extracellular plaque formation. Accordingly, we propose that one of the primary targets of therapeutic intervention should be intracellular A beta/CTF and its toxic cellular effect. We have established a cell-culture model in which the neurons degenerate on induction of endogenous expression of A beta/CTF of APP. These cultures have been used to test whether tricyclic pyrone (TP) compounds may prevent A beta/CTF-mediated neuronal death. The results to date have been encouraging. Lead compounds will now be selected for their abilities to ameliorate A beta/CTF-mediated pathology in transgenic mice. Our hope is that these compounds may eventually prove beneficial for the prevention and treatment of AD.

Amyloid-beta Leads to Impaired Cellular Respiration, Energy Production and Mitochondrial Electron Chain Complex Activities in Human Neuroblastoma Cells

“…This is of special interest, since both, Ab and CTFs, can accumulate intraneuronally. The neuronal loss and synaptic transmission deficit in AD may therefore depend on intraneuronal accumulation of Ab and CTFs (Jin et al 2002;Chang and Suh 2005). Similarly, we showed that energy production was impaired in the APP cells, which is corroborated with other findings Keil et al 2004).…”

“…This cell model attempts to mimic physiological conditions studying chronic effects of rather low concentrations of Ab that are relevant for AD patients. The fact that the mitochondrial dysfunction in our APP cell model, especially the decrease in complex IV activity, is already observed at picomolar concentrations and higher amounts of synthetic Ab are needed to achieve a comparable mitochondrial impairment also highlights the potential role of other APP fragments, e.g., the carboxy-terminal APP fragments (CTFs), which may accelerate the Ab-induced mitochondrial failure (Jin et al 2002;Chang and Suh 2005). This is of special interest, since both, Ab and CTFs, can accumulate intraneuronally.…”

Thinking outside the amyloid box

“…4 The INSERM team, led by Research Director Frédéric Checler, used an antibody that detects C99 to show that the protein fragment accumulated inside the hippocampal neurons of aging mice. The buildup occurred prior to the accumulation of extracellular Ab deposits, which are a hallmark of AD pathology.…”

Catalytic Method for Synthesis of Benzopyrano[3,2-c]chromene-6,8-dione Derivatives by Heteropoly Acids

“…[1][2][3] It is the key intermediate for various widely used oral anticoagulants and rodenticides. [4] Similarly, several derivatives of pyran or fused pyran ring systems have been shown to possess different types of biological activities [5] such as antidiabetic [6] and anti-Alzheimer [7] activities. Various other medical activities have been exhibited by pyran derivatives, including antimicrobial, [8] anti tumor, [9] anti fungal, antidepressant, [10] and platelet antiaggregating [11] activities.…”