Ap appears to be a critical component of the pathophysiological cascade that leads to dementia

The observation that all known genetic causes of AD, including PS1, PS2, APP mutations, trisomy 21, and even apoEs4, cause changes in Ap metabolism and elevated plaque deposition leads to the conclusion that Ap is central to the disease process (Selkoe 2000). Yet how Ap disrupts neural function remains uncertain.

Experiments published in the last several years have suggested different ways in which Ap might mediate neural system failure. These studies focus attention on the hypothesis that Ap-induced synaptic failure underlies neural system failure in AD, yet complexities remain: axonal, dendritic, and synaptic defects are each associated with Ap in different experimental systems. These observations include: 1) defects in axonal transport lead to dystrophic axonal processes that may both precede plaque formation and accelerate AD plaque pathology (Stokin et al. 2005); 2) spine loss occurs prominently near plaques (Spires et al. 2005; Tsai et al. 2004); 3) soluble Ap leads to diminished neuronal responsiveness (Kamenetz et al. 2003) and loss of cell surface glutamate receptors (Almeida et al. 2005; Snyder et al. 2005); and 4) infusion of (oligomeric) Ap leads to alterations in LTP and memory-related behaviors in rats (Cleary et al. 2005; Walsh et al. 2002). Finally, and perhaps most importantly, immunotherapy trials in mice (Bacskai et al. 2001; Schenk et al. 1999) and humans [with Elan AN1792] led to Ap clearance (Ferrer et al. 2004; Masliah et al. 2005a; Nicoll et al. 2003).

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