Figure 12-3. A model of Alzheimer’s disease based on the concept of synaptic element interdependence mediated by APP. The presynaptic and postsynaptic elements are interdependent and provide both trophic influences (e.g., neurotrophins, netrin-1, laminin, collagen, and synaptic activity itself) and anti-trophic influences (e.g., amyloid-β peptide). Trophic support leads to the processing of APP into three peptides that support synaptic maintenance (“wholly trinity”), whereas the withdrawal of trophic support leads to alternative processing, to four peptides that mediate synaptic inhibition, synaptic loss, neurite retraction, and ultimately, programmed cell death (“four horsemen”). In this model, the Aβ peptide functions as an antitrophin, and, because it leads to APP processing that produces additional Aβpeptide, it is “prionic” (i.e., Aβbegets additional Aβ). Reproduced from Bredesen DE, Neurodegeneration in Alzheimer’s disease: caspases and synaptic element interdependence. Mol Neurodegener. 2009;26;4:27, with permission.

the improvement in AD model mice that occurs with a reduction in tau protein.

An alternative model, presented in Figure 12-3, argues that APP is indeed a dependence receptor and that it functions normally as a molecular switch in synaptic element interdependence: in this model, both the presynaptic element and the postsynaptic element are dependent on trophic support, which includes soluble factors such as netrin, substrate molecules such as laminin, neurotransmitters, and neuronal activity, as well as other factors. In the presence of adequate trophic support, APP is cleaved at the alpha and gamma sites, generating three peptides – sAPPα, p3, and APP intracellular cytoplasmic/C-terminal domain (AICD) – that support cell survival and synaptic maintenance. However, a reduction in trophic support alters the processing of APP, reducing the α/β ratio of cleavage, and leading to the production of four peptides – sAPPβ, Aβ, Jcasp, and C31 – that mediate a reduction in synaptic transmission, synaptic loss, neurite retraction and, ultimately, programmed cell death. In this model, Alzheimer’s disease is suggested to be an imbalance in physiologic

signaling pathways that mediate synaptic maintenance versus synaptic reorganization, mediated at least in part by APP, functioning in synaptic element interdependence, as part of a plasticity module that includes other receptors such as the common neurotrophin receptor, p75NTR.

Caspase cleavage also appears to play an important role in cytotoxicity induced by multiple polyglutamine proteins, such as huntingtin, atrophin-1, ataxin-3, and androgen receptor. In the case of huntingtin, recruitment of caspase-2 into a complex with huntingtin was found to be polyglutamine length-dependent, leading to cleavage at Asp552 both in vitro and in vivo. Although huntingtin is not a surface receptor like APP, the upregulation of caspase-2 observed in Huntington’s model mice correlated directly with decreased levels of brainderived neurotrophic factor, suggesting that huntingtin may indeed represent a mediator of cellular dependence on trophic support. Furthermore, results analogous to those obtained with the caspase-uncleavable APP mutant described above were obtained with the caspase-6-uncleavable huntingtin mutant. In that study, the yeast artificial chromosome transgenic mouse model of Huntington’s disease was used, and the Huntington’s phenotype was prevented by mutating the caspase-6 cleavage site, but not by mutating the caspase-3 cleavage sites within the huntingtin protein. Altogether, these observations argue that a central component of the apoptosis machinery, caspases, play a critical role in generating the pathological fragments of APP, Huntingtin, and other toxic proteins associated with neurodegenerative diseases.

ACKNOWLEDGMENT

We thank Molly Susag, Loretta Sheridan, and Rowena Abulencia for manuscript preparation and members of the Bredesen laboratory for discussion and critical reading of the manuscript.

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