Preclinical Studies of PPARy Agonists in Animal Models of AD

There have been four studies investigating the effects of PPARy agonists in murine models of AD. The first of these studies investigated the effects of pi-oglitazone in Tg2576 mice that overexpress a mutant form of APP 86 . This study employed 12-month-old Tg2576 mice with established plaque pathology which were then treated with the drug for 4 months. These animals were treated with oral pioglitazone at a dosage of 120 ppm (20 mg kg day) in standard chow. Pioglitazone was used in these studies...

Cu homeostasis in Alzheimers disease brain

Cu is normally found at relatively high levels in the brain (100-150 M) with substantial variations at the cellular and subcellular level 55-57 . Ionic Cu is compartmentalized into a post-synaptic vesicle and released upon activation of the NMDA-R but not AMPA kainate-type glutamate receptors 58 . The Menkes Cu7aATPase is the vesicular membrane Cu transporter, and upon NMDA-R activation, it traffics rapidly and reversibly to neuronal processes, independent of the intracellular Cu concentration...

Etiology and Environmental Risk Factors for AD

The etiology of AD remains largely elusive. A small percentage (5 -10 ) of all AD cases can be ascribed to genetic mutations and has an early onset age (< 65). The large majority (90-95 ), however, is considered sporadic and has a late onset. Thus, aging is the biggest risk factor for AD. A myriad of environmental factors that increase with age may play an important role in AD. It is unclear if these factors can be converged to one common underlying mechanism or if they are independent events...

Targeting Amyloid Pathologies

According to the predominant amyloid cascade hypothesis, Aft peptides are the ultimate perpetrator of AD. Understandably, most of the drug discovery efforts are targeted towards reducing their levels in the brain. This is achieved by either decreasing production or increasing clearance. Aft peptides are produced by concerted proteolytic cleavage of their substrate, amyloid precursor protein (APP), by BACE1 (ft-secretase) and y-secretase. These two proteases have thus become the targets of...

Apolipoproteins

Prior studies have indeed shown that atorvastatin treatment in AD significantly lowers plasma ApoE levels 152 . This is in agreement with other reports demonstrating statin lowering of ApoE levels 153,154 . Decreases in ApoE might, upon first glance, appear to impede A 3 clearance to the bloodstream as recent reports show A 40 can be cleared through LRP1-ApoE interactions and A 3 42 through LRP2-ApoJ 104 . However, excess ApoE has also been hypothesized to impede LTP and stimulate tau...

Therapeutic Potential of GSK3 Inhibitors

The current therapeutics for Alzheimer's disease are limited to drugs that provide only marginal symptomatic benefit in the clinic. This is achieved by attenuating cognitive deficits through inhibiting acetylcholinesterase and increasing the levels of the neurotransmitter ACh or by antagonists for the NMDA receptor. However, this type of therapy does not affect the underlying pathology or halt the progressive neuritic dystrophy and neuronal damage. In addition, over time these therapies become...