Tracing the signals: Unravelling neuron-glia interactions in Alzheimer’s disease

Abstract

Alzheimer's disease pathologyAlzheimer's disease (AD) was first discovered in 1901 and reported on in 1906 by Alois Alzheimer (Alzheimer, 1907). Today, AD constitutes the largest known form of dementia, with current estimates ranging from 25 to 50 million people suffering from AD worldwide . AD patients either suffer from familial AD or develop AD on an sporadic basis (Lane et al., 2018). The familial form is caused by specific missense mutations in the amyloid-β protein precursor (APP) and PSEN1/PSEN2 and symptoms usually develop between the age of 30 and 50 (Bateman et al., 2010). Sporadic late-onset AD, however, is expected to develop due to a complex interplay between genetic and environmental factors (Marques & Outeiro, 2013). Biologically, AD is a neurodegenerative disease that is characterized by pathological hallmarks, such as reactive gliosis and the accumulation of amyloid-ß (Aß) peptides and phosphorylation of tau protein, resulting in the presence of Aß plaques and neurofibrillary tangles (NFTs), respectively (fig. 1a) . The tau protein family is a group of proteins that is almost exclusively present in neurons. They interact with microtubules and function as important modulators of axonal stability (Buee et al., 2000). The excessive or abnormal phosphorylation of tau protein, as present in AD, results in the formation of NFTs, microtubule dysfunction, and ultimately neuronal death. Early reports on the pathogenesis of AD indicate that NFTs are specific for late-stage disease progression (Braak & Braak, 1991. The initial phase of AD development is typically characterized by the accumulation of Aß peptides . Aß peptides are derivatives of cleavage of the APP, which is a transmembrane protein abundantly expressed by neurons, particularly at the synapse (fig. 1b) (Zheng & Koo, 2006). The APP is considered important for synaptic transmission and its expression is strictly regulated. Up-or downregulation of the APP negatively impacts synaptic plasticity and cognitive performance, as indicated by reduced performance on behavioural paradigms and impaired levels of long-term potentiation (