The keystone of Alzheimer pathogenesis might be sought in Aβ physiology

Abstract

For several years Amyloid-beta peptide (Aβ) has been considered the main pathogenetic factor of Alzheimer's disease (AD). According to the so called Amyloid Cascade Hypothesis the increase of Aβ triggers a series of events leading to synaptic dysfunction and memory loss as well as to the structural brain damage in the later stage of the disease. However, several evidences suggest that this hypothesis is not sufficient to explain AD pathogenesis, especially considering that most of the clinical trials aimed to decrease Aβ levels have been unsuccessful. Moreover, Aβ is physiologically produced in the healthy brain during neuronal activity and it is needed for synaptic plasticity and memory. Here we propose a model interpreting AD pathogenesis as an alteration of the negative feedback loop between Aβ and its physiological receptors, focusing on α7-nAchRs. According to this vision, when Aβ cannot exert its physiological function a negative feedback mechanism would induce a compensatory increase of its production leading to an abnormal accumulation that reduces α7-nAchR function, leading to synaptic dysfunction and memory loss. In this perspective, the indiscriminate Aβ removal might worsen neuronal homeostasis, causing a further impoverishment of learning and memory. Even if further studies are needed to better understand and validate these mechanisms, we believe that to deepen the role of Aβ in physiological conditions might represent the keystone to elucidate important aspects of AD pathogenesis.

Major amyloid-β–degrading enzymes, endothelin-converting enzyme-2 and neprilysin, are expressed by distinct populations of GABAergic interneurons in hippocampus and neocortex

“…The half-life of the peptide in brain is between 0.5 and 3 hours (Basak, et al, 2012) and disruption of the activities of Aβ degrading proteases through pharmacological inhibition or genetic inactivation results in increased steady-state levels of endogenous Aβ in the brains of mice (Pacheco-Quinto, et al, 2013). This complex regulation of both Aβ production and degradation strongly supports a key physiological function for the peptide and mounting evidence indicates that Aβ is important for synaptic plasticity and cognition (reviewed in (Puzzo, et al, 2015). The enzymes responsible for degrading Aβ could therefore be viewed as regulators of normal Aβ function and would be expected to concentrate in the microenvironments where Aβ fulfills its function.…”

Neonicotinoid Insecticides Alter the Gene Expression Profile of Neuron-Enriched Cultures from Neonatal Rat Cerebellum

“…In the brain, the α7 nAChR plays important functions; synaptic plasticity, regulation of neuronal growth, differentiation, and enhancing memory and cognition [62,63,64]. Furthermore, α7 nAChR dysfunction is correlated to the symptoms and etiology of Alzheimer disease [65,66] and schizophrenia [21,67]. …”

Amyloid beta: structure, biology and structure-based therapeutic development

“…They increase with age, even in healthy subjects, and the number of plaques in healthy controls is often comparable with the number found in age-matched affected individuals [233] . Moreover, β-amyloid is physiologically produced in healthy brains during neuronal activity and is necessary for synaptic plasticity and memory [234] . Furthermore, in the AD population, there is only a weak correlation between the number of senile plaques and the severity of the pathology.…”