The relationships between neuroglial and neuronal changes in Alzheimer's disease, and the related controversies II: gliotherapies and multimodal therapy

Abstract

Since the original description of Alzheimer´s disease (AD), research into this condition has mainly focused on assessing the alterations to neurons associated with dementia, and those to the circuits in which they are involved. In most of the studies on human brains and in many models of AD, the glial cells accompanying these neurons undergo concomitant alterations that aggravate the course of neurodegeneration. As a result, these changes to neuroglial cells are now included in all the "pathogenic cascades" described in AD. Accordingly, astrogliosis and microgliosis, the main components of neuroinflammation, have been integrated into all the pathogenic theories of this disease, as discussed in this part of the two-part monograph that follows an accompanying article on gliopathogenesis and glioprotection. This initial reflection verified the implication of alterations to the neuroglia in AD, suggesting that these cells may also represent therapeutic targets to prevent neurodegeneration. In this second part of the monograph, we will analyze the possibilities of acting on glial cells to prevent or treat the neurodegeneration that is the hallmark of AD and other pathologies. Evidence of the potential of different pharmacological, non-pharmacological, cell and gene therapies (widely treated) to prevent or treat this disease is now forthcoming, in most cases as adjuncts to other therapies. A comprehensive AD multimodal therapy is proposed in which neuronal and neuroglial pharmacological treatments are jointly considered, as well as the use of new cell and gene therapies and non-pharmacological therapies that tend to slow down the progress of dementia.

Keywords: AD multimodal treatment; Alzheimer´s disease; astroglia; astrogliosis; cell therapy; gene therapy; gliotherapy; microglia; microgliosis; neuroglia; oligodendroglia; pharmacological therapy.

Figure 1.

Scheme on the various therapeutic possibilities in AD and the role of glyotherapy. The upper left image shows a representation of the adaptive interplay of normal neurons––neuroglial cells to maintain optimal function of neural circuits in normal scenario of the nervous tissue (adapted from Toledano et al). The upper right image shows a representation of the nervous tissue in AD after undergoing neuroinflammation and neurodegeneration processes. Multimodal AD therapies, against neuroinflammation and neurodegeneration, include: 1. Neuronal defense/repair; 2. Gliotherapy; and 3. AD prevention (pharmacological and non-pharmacological). There are several important lines of gliotherapy, some of them currently under study (pharmacological interventions, cell and gene therapies) that may be of paramount importance in the coming years. A (Astrocyte); Dn (Dystrophic neurites); HA (Hypertrophic astrocyte); HM (Hypertrophic microglial cell); HMf (Hypertrophic microglial cell, phagocytic subtype); M (Microglial cell); Npre (Presynaptic Neuron); Npost (postsynaptic neuron); NT (Neurofibrillary tangles); P (Amyloid plaques); R (Receptors for specific.