Roles of amyloid precursor protein family members in neuroprotection, stress signaling and aging

Abstract

The roles of amyloid precursor protein (APP) family members in normal brain function are poorly understood. Under physiological conditions the majority of APP appears to be processed along the non-amyloidogenic pathway leading to the formation of the secreted N-terminal APP fragment sAPPα. This cleavage product of APP has been implicated in several physiological processes such as neuroprotection, synaptic plasticity, neurite outgrowth and synaptogenesis. In this review we focus on the role of APP family members in neuroprotection and summarize the cellular and molecular mechanisms which are believed to mediate this effect. We propose that a reduction of APP processing along the non-amyloidogenic pathway during brain aging could result in an enhanced susceptibility of neurons to cellular stress and could contribute to neurodegeneration in Alzheimer's disease.

The reaction of cerebral cortex to a nearby lesion: Damage, survival, self-protection

“…Neuroglobin labelling is red; NeuN labelling is green; blue is nuclear counterstaining with bisbenzimide. The scale in C 1 refers to A 1, 2,3,4 and B 1 ; the scale in C 2 refers to B 2 , D and E. Robinson, 2003;Castellani et al, 2006;Thornton et al, 2006;Castellani and Smith, 2011;Corrigan et al, 2011;Kogel et al, 2012). The present results, which show cell survival under stress, with APP and Aβ expression raised, give some support to the interpretation of APP and Aβ as neuroprotective.…”

Comparative analysis of single and combined APP/APLP knockouts reveals reduced spine density in APP-KO mice that is prevented by APPsα expression

“…In the competing non-amyloidogenic pathway that is meditated by α-secretase, APP cleavage occurs at a membrane-proximal site within the Aβ region. Thus, α-secretase processing not only precludes the formation of Aβ peptides but also liberates the large soluble, neuroprotective ectodomain APPsα that is secreted into the extracellular space [1-3]. Classically, synapse loss in AD has mainly been attributed to the synaptotoxic effects of various Aβ species.…”

Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease

“…The APP membrane receptor is involved in the regulation of neuronal activity, synaptic function, neurogenesis, and metal homeostasis. [20][21][22][23][24] APP undergoes proteolytic processing through two alternative cellular metabolic pathways, as illustrated in Figure 1. Aβ is produced through the so-called amyloidogenic pathway.…”