Signaling effect of amyloid-β42 on the processing of AβPP

Abstract

The effects of amyloid-β are extremely complex. Current work in the field of Alzheimer disease is focusing on discerning the impact between the physiological signaling effects of soluble low molecular weight amyloid-β species, and the more global cellular damage that could derive from highly concentrated and/or aggregated amyloid. Being able to dissect the specific signaling events, to understand how soluble amyloid-β induces its own production by upregulating BACE1 expression, could lead to new tools to interrupt the distinctive feedback cycle with potential therapeutic consequences. Here we describe a positive loop that exists between the secretases that are responsible for the generation of the amyloid-β component of Alzheimer disease. According to our hypothesis, in familial Alzheimer disease, the primary overproduction of amyloid-β can induce BACE1 transcription and drive a further increase of amyloid-β precursor protein processing and resultant amyloid-β production. In sporadic Alzheimer disease, many factors, among them oxidative stress and inflammation, with consequent induction of presenilins and BACE1, would activate a loop and proceed with the generation of amyloid-β and its signaling role onto BACE1 transcription. This concept of a signaling effect by and feedback on the amyloid-β precursor protein will likely shed light on how amyloid-β generation, oxidative stress, and secretase functions are intimately related in sporadic Alzheimer disease.

Biomarkers of Alzheimer Disease, Insulin Resistance, and Obesity in Childhood

“…According to the "amyloid cascade hypothesis," the longer and more fibrillogenic form of Abs, the Ab42, deposits and forms senile plaques and then neurofibrillary tangles, leading to neuronal cell death, and ultimately dementia. 15 There are almost 200 mutations in APP, 16 PSEN1 and 2 genes that are known to lie behind most early-onset familial forms of AD. 17 They all act by shifting the intramembranous cleavage of APP within the catalytic site of g-secretase, 18 therefore increasing the ratio between the 2 isoforms Ab42 and Ab40, causing the aberrant secretion of longer Ab species 19 that ultimately form neurotoxic Ab oligomers.…”

Omega-3 Essential Fatty Acids Modulate Initiation and Progression of Neurodegenerative Disease

“…Pathogenic processes which characterize AD neuropathology exhibit four consistent features: (a) they are progressive with aging; (b) they act in a chronic, cooperative, and integrative fashion; (c) they are highly specific to the neurons of the association neocortex, hippocampus which constitute the evolutionarily recent limbic system of the human brain; and (d) once initiated, the pathogenic effects of these processes exhibit positive feedback, perpetuating until brain cell defenses are exhausted, culminating in the irreversible degeneration and death of neurons. Mitochondrial dysfunction and focused oxidative damage, including peroxidation of membrane lipids and PUFAs by ROS and heightened pro-inflammatory gene expression, appear to be among the earliest events in AD affected tissues [39][40][41][42][43][44][45]. The ∼110 kDa integral type-1 transmembrane glycoprotein beta-amyloid precursor protein (βAPP) holoprotein, central to the 'amyloid cascade hypothesis' of AD, and the generation of neurotoxic Aβ peptides 37 to 43 amino acids in length (Aβ37-Aβ43) from βAPP via the tandem actions of the 'beta-gammasecretase systems' appear to be intimately involved with these oxidative stress, pro-inflammatory signaling, and proapoptotic events [44,45].…”

“…Mitochondrial dysfunction and focused oxidative damage, including peroxidation of membrane lipids and PUFAs by ROS and heightened pro-inflammatory gene expression, appear to be among the earliest events in AD affected tissues [39][40][41][42][43][44][45]. The ∼110 kDa integral type-1 transmembrane glycoprotein beta-amyloid precursor protein (βAPP) holoprotein, central to the 'amyloid cascade hypothesis' of AD, and the generation of neurotoxic Aβ peptides 37 to 43 amino acids in length (Aβ37-Aβ43) from βAPP via the tandem actions of the 'beta-gammasecretase systems' appear to be intimately involved with these oxidative stress, pro-inflammatory signaling, and proapoptotic events [44,45].…”

Amyloid and Alzheimer’s disease

“…In a proposed positive feedback loop, Aβ can have signaling effect on the transcription of BACE1, a candidate β secretase (Tabaton et al, 2010). This can be achieved by the activation of G-protein coupled receptors (GPCR) or calcium ion channels, or the inhibition of insulin receptors.…”