Tau-Mediated Dysregulation of Neuroplasticity and Glial Plasticity

Abstract

The inability of individual neurons to compensate for aging-related damage leads to a gradual loss of functional plasticity in the brain accompanied by progressive impairment in learning and memory. Whereas this loss in neuroplasticity is gradual during normal aging, in neurodegenerative diseases such as Alzheimer's disease (AD), this loss is accelerated dramatically, leading to the incapacitation of patients within a decade of onset of cognitive symptoms. The mechanisms that underlie this accelerated loss of neuroplasticity in AD are still not completely understood. While the progressively increasing proteinopathy burden, such as amyloid β (Aβ) plaques and tau tangles, definitely contribute directly to a neuron's functional demise, the role of non-neuronal cells in controlling neuroplasticity is slowly being recognized as another major factor. These non-neuronal cells include astrocytes, microglia, and oligodendrocytes, which through regulating brain homeostasis, structural stability, and trophic support, play a key role in maintaining normal functioning and resilience of the neuronal network. It is believed that chronic signaling from these cells affects the homeostatic network of neuronal and non-neuronal cells to an extent to destabilize this harmonious milieu in neurodegenerative diseases like AD. Here, we will examine the experimental evidence regarding the direct and indirect pathways through which astrocytes and microglia can alter brain plasticity in AD, specifically as they relate to the development and progression of tauopathy. In this review article, we describe the concepts of neuroplasticity and glial plasticity in healthy aging, delineate possible mechanisms underlying tau-induced plasticity dysfunction, and discuss current clinical trials as well as future disease-modifying approaches.

Keywords: Alzheimer’s disease; glial plasticity; synaptic plasticity; tauopathy; therapeutics.

Figure 1

Neuroplasticity can be assessed at different levels. Structural plasticity refers to the morphological changes that occur at the synapse, such as altered dendritic spine density, dendritic spine shape, and synaptic protein profiles (A). Functional plasticity affects neuronal circuit regulation and includes processes such as long-term potentiation (LTP), long-term depression (LTD), and homeostatic scaling (B). At the organ level, network plasticity modulates learning, memory, cognition, and resilience (C). Proper function and careful integration of all levels of plasticity are required for healthy brain function.

Figure 2

Pathological changes and biomarker alterations observed in the development of Alzheimer’s disease (AD). Moving left to right: schematic depicting brain alterations in a cognitively normal individual (A), in an mild cognitive impairment (MCI) individual (B), and in an end-stage AD patient (C). Amyloid β (Aβ) pathology begins in the frontal cortex and spreads throughout the brain (blue arrows). Neurofibrillary tangle (NFT) pathology begins in the medial temporal cortex and locus coeruleus and spreads to the rest of the brain (green arrows). Gliosis increases with age, and the onset of the disease leads to maladaptive gliosis and eventual chronic glial activation and dysfunction. Biomarker alterations corresponding to each stage are listed under (A,B) in black boxes. Abnormal changes in the frontal and temporal lobes as well as changes observed in an aged brain are listed in (C) in green, orange, and blue boxes, respectively.

Figure 3

Phosphorylated tau vs. neurofibrillary tangle (NFT) tau species determine microglial and astroglial phenotype. Immunohistochemical detection of phosphorylated tau (CP13 antibody, pSer202 tau epitope), NFT tau (histological Gallyas silver stain), microglia (Iba1 antibody), and astrocytes (GFAP antibody) in the cortex of 3-month-old nontransgenic (C57/Bl6) mice that received neonatal intracerebroventricular delivery of adeno-associated virus (AAV) expressing P301L tau or P301L/S320F tau compared to age-matched naive C57/Bl6 control mice. AAV-P301L tau expressing mice accumulate intracellularly and neuropil phosphorylated tau (ptau; E), while in the AAV-P301L/S320F tau expressing mice, ptau is concentrated in the somatodendritic compartment (I). No ptau is observed in control (A). Histological Gallyas silver stain indicates frank NFT pathology only in the AAV-P301L/S320F tau mice (J), and not in the AAV-P301L tau mice (F) or control group (B). Detection of microglia (Iba1 antibody) and astrocytes (GFAP antibody) reveals increased hypertrophy of microglia and astrocytes in the AAV-P301L/S320F tau mice (K,L) compared to the AAV-P301L tau (G,H) and control mice (C,D). Scale bar: 50 μm.

Figure 4

Glial and neuronal function and plasticity are dysregulated in AD. Schematics depicting healthy glial and neuronal function (A) compared to AD-induced glial and neuronal dysfunction (B). Normal communication and support processes occur between neurons, astrocytes, microglia, and oligodendrocytes even in the presence of Aβ plaques and oligomers (A). In AD, healthy communication and function break down between neurons, astrocytes, microglia, and oligodendrocytes (B). Astrocytes and microglia take up tau, Aβ, and synaptic boutons; tau oligomers spread across synapses and travel between different cell types (neurons, astrocytes, microglia, and oligodendrocytes); neurons develop NFT deposits, and Aβ plaques convert to neuritic plaques and cause the death of neurites (B). Listed below the schematics are dysregulated processes seen in a normally functioning brain (A) compared to an AD brain (B). The key for the schematics is located on the right side of the figure.