Astrocytic transporters in Alzheimer's disease

Abstract

Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.

TSPO and amyloid deposits in sub-regions of the hippocampus in the 3xTgAD mouse model of Alzheimer’s disease

“…Post-mortem human studies suggest that TSPO is both astrocytic and microglial (Cosenza-Nashat et al, 2009;Venneti et al, 2009). The activation of both cell types in the disease has been demonstrated (Heneka et al, 2015;Ugbode et al, 2017). In the present report, we showed an elevated colocalization of TSPO with microglia and to a lesser degree some TSPO expression in astrocytes suggesting that TSPO may not exclusively have a microglial origin in 3xTgAD mice.…”

The Increased Densities, But Different Distributions, of Both C3 and S100A10 Immunopositive Astrocyte-Like Cells in Alzheimer’s Disease Brains Suggest Possible Roles for Both A1 and A2 Astrocytes in the Disease Pathogenesis

“…AD is the commonest cause of neurodegeneration in the west, and whilst historically researchers have concentrated on the direct toxicity of Aβ and hyperphosphorylated tau on the neurons, recently much more attention has been paid to the role microglial cells and astrocytes play in neuronal dysfunction and loss [6][7][8]13]. Considering that astrocytes are an abundant cell type in the CNS and their role has been thought to be very important in metabolic support and the protection of neurons [11], it is now being appreciated that astrocytic dysfunction may have a primary role in the pathogenesis of neurodegenerative diseases [9].…”

“…Whilst most research into this disease has concentrated on neuronal dysfunction and the pathophysiological roles of the associated abnormal proteins, more recently, attention has been paid to the contribution of astrocytic activity to the disease progression [ 6 , 7 , 8 , 9 ]. Astrocytes are abundant in the central nervous system [ 10 ], and their role was considered previously to be primarily supportive of the neuron as acting like a “brain glue” [ 7 , 11 ], but there is now accumulating evidence that, depending on the disease stage, they may be involved in the production of toxic Aβ, synaptic loss and neuronal cell death [ 8 , 12 , 13 ]. Indeed, studies in animal models of AD have shown that astrocyte activation can actually precede Aβ deposition [ 14 ].…”

YKL-40 in the brain and cerebrospinal fluid of neurodegenerative dementias

“…However, the precise regional and temporal contribution of glial activation to the pathogenic process is far from understood. Similar to microglial activation, sustained astrocytic activation may lead to a switch from a neuroprotective and neurotrophic to a neurodegenerative phenotype, increasing neuronal vulnerability to chemokines, pro-inflammatory cytokines and reactive oxygen species [ 68 – 70 ]. This is exemplified by proteins such as S100B, which is released from astrocytes with neurotrophic or neurotoxic effects on neurons depending on their concentration and on the astrocytic activation state [ 71 , 72 ].…”