Abstract
It is estimated that Alzheimer’s disease (AD) affects tens of millions of people, comprising not only suffering patients, but also their relatives and caregivers. AD is one of age-related neurodegenerative diseases (NDs) characterized by progressive synaptic damage and neuronal loss, which result in gradual cognitive impairment leading to dementia. The cause of AD remains still unresolved, despite being studied for more than a century. The hallmark pathological features of this disease are senile plaques within patients’ brain composed of amyloid beta (Aβ) and neurofibrillary tangles (NFTs) of Tau protein. However, the roles of Aβ and Tau in AD pathology are being questioned and other causes of AD are postulated. One of the most interesting theories proposed is the causative role of amyloid β oligomers (AβOs) aggregation in the pathogenesis of AD. Moreover, binding of AβOs to cell membranes is probably mediated by certain proteins on the neuronal cell surface acting as AβO receptors. The aim of our paper is to describe alternative hypotheses of AD etiology, including genetic alterations and the role of misfolded proteins, especially Aβ oligomers, in Alzheimer’s disease. Furthermore, in this review we present various putative cellular AβO receptors related to toxic activity of oligomers.
Highlights
Alzheimer’s disease (AD) affects tens of millions of people worldwide and estimated number of AD patients would increase to over 130 million by 2050 [1]
It was demonstrated that soluble amyloid β oligomers (AβOs) could inhibit long-term potentiation (LTP) in mouse hippocampal tissue samples, suggesting that this form of amyloid β (Aβ) might be the species triggering loss of synapses and memory impairment in AD [64]. It was shown in mice model of AD that transgenic animals overexpressing mutant form of human amyloid precursor protein (APP) exhibited lower density of presynaptic terminals, as well as severe impairments in synaptic transmission in the hippocampus for months before the presence of amyloid plaques [65]. This toxic activity of oligomers was confirmed in the study of Shankar et al, who demonstrated that soluble AβOs isolated from AD patients’ brains decreased number of synapses in animal models of AD, leading to enhanced long-term synaptic depression (LTD) and LTP in regions of brain which are responsible for memory [51]
Triggering receptor expressed on myeloid cells 2 (TREM2)-DNAX-activating protein of 12 kDa (DAP12) interaction was enhanced by AβOs, which demonstrates that TREM2 may act as a microglial AβO receptor that mediates physiological and AD-related pathological effects [181]
Summary
Alzheimer’s disease (AD) affects tens of millions of people worldwide and estimated number of AD patients would increase to over 130 million by 2050 [1]. The main histopathological hallmarks of AD are the extracellular plaques within brain tissue consisted of variant forms of amyloid β (Aβ) and neurofibrillary tangles (NFTs) of many forms of phosphorylated Tau proteins (pTau), localized intraneuronally [3]. These pathological alterations are seen within medial temporal lobe, whereas in later stages of AD they progress subsequently to brain regions associated with neocortex [4,5]. Declined levels of Aβ42 in cerebrospinal fluid (CSF) and the presence of Aβ plaques in neuroimaging may head other AD-related alterations by many years [7]
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