The established and emerging roles of astrocytes and microglia in amyotrophic lateral sclerosis and frontotemporal dementia

Rowan A Radford, Marco Morsch, Stephanie L Rayner, Nicholas J Cole, Dean L Pountney, Roger S Chung, Rowan A Radford, Marco Morsch, Stephanie L Rayner, Nicholas J Cole, Dean L Pountney, Roger S Chung

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two progressive, fatal neurodegenerative syndromes with considerable clinical, genetic and pathological overlap. Clinical symptoms of FTD can be seen in ALS patients and vice versa. Recent genetic discoveries conclusively link the two diseases, and several common molecular players have been identified (TDP-43, FUS, C9ORF72). The definitive etiologies of ALS and FTD are currently unknown and both disorders lack a cure. Glia, specifically astrocytes and microglia are heavily implicated in the onset and progression of neurodegeneration witnessed in ALS and FTD. In this review, we summarize the current understanding of the role of microglia and astrocytes involved in ALS and FTD, highlighting their recent implications in neuroinflammation, alterations in waste clearance involving phagocytosis and the newly described glymphatic system, and vascular abnormalities. Elucidating the precise mechanisms of how astrocytes and microglia are involved in ALS and FTD will be crucial in characterizing these two disorders and may represent more effective interventions for disease progression and treatment options in the future.

Keywords: amyotrophic lateral sclerosis; astrocyte; frontotemporal dementia; glymphatic; microglia; neuroinflammation; phagocytosis; vasculature.

Figures

Figure 1
Figure 1
Genetic and pathological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). (A) Familial and sporadic genetic mutations were linked to the clinical phenotypes on the ALS (blue) and FTD (red) spectrum. Genes are plotted according to their hypothesized mechanism in relation to disease (top to bottom). (B) Pathological protein inclusions are a hallmark of ALS and FTD, reflecting the significant overlap on the disease spectrum. FUS (Red) and TDP-43 (Blue) inclusions are found in both ALS and FTD. Predominate SOD1 (Pink) and Tau (Green) is more indicative of ALS and FTD respectively. FTD-UPS (Yellow) is found in ~1% of cases and represent cases of familial CHMP2B mutations.
Figure 2
Figure 2
Phagocytic dysfunction and the glymphatic pathway and its (potential) involvement in ALS and FTD. (A) Three genes (TREM2, GRN and PFN1) which link microglial phagocytic dysfunction to ALS and FTD and their effect on microglial phenotype. All three are predicted loss of function mutations which decrease the phagocytic capacity of microglia. Depending on the type of mutation/s to these genes different neurodegenerative conditions can arise, while variants cause increase risk of developing neurodegenerative conditions or worsen prognosis. Neuronal Ceroid Lipofuscinosis is a type of neurodegenerative lysosomal disorder which has been reported in patients PRGN null patients (Petkau and Leavitt, 2014). AD, Alzheimer’s disease; PD, Parkinson’s disease; MS, multiple sclerosis. (B) In the normal CNS, CSF circulates in a perivascular compartment driven by arterial pulse pressure. Astrocytic endfeet cover the perivascular space and facilitate movement of CSF into the parenchyma largely via AQP4. This fluid flow through the interstitial space allows the removal of debris from the extracellular space before draining into venous perivascular compartments. Microglia also remove potentially toxic waste via phagocytosis and dysfunctional microglial phagocytosis is linked to ALS and FTD pathogenesis (see A). In the CNS of ALS and FTD patients, glymphatic function and microglial phagocytosis may be compromised and contribute to neurodegeneration. Reactive astrocytes conceivably lose AQP4 polarization and express it elsewhere. This may lead to turbulent flow through the interstitium. Cerebral vascular function is reduced in patients which could potentially lead to decreased pressure for glymphatic function. A, astrocytes; M, microglia; N, neuron; CSF, cerebrospinal fluid.

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