Exploring glia to better understand Alzheimer’s disease

Abstract

The amyloid-β (Aβ) hypothesis has been the leading explanation for the pathogenesis of Alzheimer’s disease (AD). The most common traits of AD are cognitive impairments and memory loss, which are associated with the accumulation of Aβ. Aβ aggregates activate glial cells, which in turn remove Aβ. Because microglia act as immune cells in the brain, most glia-related studies of AD have focused primarily on this cell type. However, astrocytes, another type of glial cell, also participate in the brain immune system, synaptic formation, brain homeostasis, and various other brain functions. Accordingly, many studies on the underlying mechanisms of AD have investigated not only neurons but also glial cells. Although these studies suggest that microglia and astrocytes are effective targets for AD therapeutics, other recent studies have raised questions regarding whether microglial cells and/or astrocytes serve a neuroprotective or neurotoxic function in AD. To gain a better understanding of the mechanisms of AD and identify novel targets for AD treatment, in this review, we consider the role of both microglia and astrocytes in AD.

Predictive Potential of Circulating Ube2h mRNA as an E2 Ubiquitin-Conjugating Enzyme for Diagnosis or Treatment of Alzheimer’s Disease

“…The AD pathology is mainly characterized in the cerebral cortex and hippocampus, and extensively connected with other neurodegenerative disorders such as PD [24,25]. Traditionally, clinical examinations, including blood tests, brain structural imaging and family history, have been used to determine the symptoms for AD.…”

A unified model of dementias and age‐related neurodegeneration

“…In AD, there has been a growing, if informal, consensus that a more fundamental upstream mechanism underlies the pathognomonic findings. The mechanism is often attributed to glial cell dysfunction, although there is no agreement on the glial cell changes that result in downstream findings . This type of model (Figure ) can be represented by a single fundamental upstream mechanism causing multiple downstream findings, including amyloid plaque, tau tangles, mitochondrial dysfunction, lipid processing, TDP‐43 proteinopathy, immune function, and synaptic loss …”

“…The mechanism is often attributed to glial cell dysfunction, [28][29][30][31][32][33] although there is no agreement on the glial cell changes that result in downstream findings. [34][35][36][37][38] This type of model ( Figure 3) can be represented by a single fundamental upstream mechanism causing multiple downstream findings, including amyloid plaque, tau tangles, mitochondrial dysfunction, 39 lipid processing, 40 TDP-43 proteinopathy, 41 immune function, and synaptic loss. 42 A more general model would encompass all dementias, offering an underlying and shared upstream mechanism expressed variably in specific dementias.…”

Promising molecular targets for pharmacological therapy of neurodegenerative pathologies

“…Many of these disorders are proteinopathies and are characterized by an accumulation of specific protein deposits, in particular Aβ in Alzheimer’s [ 48 ], resulting in the activation of immunocompetent brain cells and subsequent inflammatory reactions [ 49 , 50 ]. Thus, it has been shown that activated cells can both reduce the amount of Aβ and increase its toxic effect [ 48 , 51 , 52 ].…”

“…Considering the neuroprotective role of astrocytes, it should be mentioned that the proinflammatory cytokines TNF-α, TGF-β, and IL-1β are released by cells at an early response, they subsequently activate adjacent microglial cells, and also degrade soluble Aβ with the help of apolipoproteins and, to a larger extent, ApoE2. Therefore, it is believed that astrocytes can act as a therapeutic target in Alzheimer’s [ 51 ]. Yet, neuroinflammation primarily disrupts the cytokine balance and changes the microenvironment; hence, some glial cells may have a pro-inflammatory function.…”