Astrocytes in Alzheimer's Disease
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Questions and Answers

What was realized by Alois Alzheimer in the context of dementia?

  • The pathological potential of astroglia (correct)
  • The negligible role of astroglia
  • The presence of only senile plaques
  • The therapeutic potential of astroglia

    • In which mouse model are astrocytes observed to undergo complex morphological changes?

  • Triple transgenic 3xTg-AD mouse (correct)
  • Single transgenic 1xTg-AD mouse
  • Quadruple transgenic 4xTg-AD mouse
  • Double transgenic 2xTg-AD mouse

    • What is expressed by a decrease in the GFAP-positive astroglial profiles?

  • Astroplasticity
  • Astroreactivity
  • Astrodegeneration (correct)
  • Astrohypertrophy

    • At which stage do astrocytes in hippocampus, prefrontal and entorhinal cortices demonstrate signs of atrophy and astrodegeneration?

    <p>Early pre-symptomatic stages</p> Signup and view all the answers

    In which region were the earliest signs of atrophy observed?

    <p>Entorhinal cortex</p> Signup and view all the answers

    What is a characteristic of astrodegeneration in astrocytes?

    <p>Decreased somata volume</p> Signup and view all the answers

    At which age do astrocytes in the hippocampus demonstrate signs of atrophy and astrodegeneration?

    <p>9-12 months</p> Signup and view all the answers

    What is the pattern of atrophic changes in astrocytes?

    <p>Particular and spatiotemporal</p> Signup and view all the answers

    What is the primary function of the vesicular trafficking system in astrocytes?

    <p>To secrete peptides and amino acid transmitters to the cell surface</p> Signup and view all the answers

    What is the effect of an increase in [Ca2+]i on glutamatergic vesicle motility?

    <p>It accelerates the motility of glutamatergic vesicles</p> Signup and view all the answers

    What is a characteristic feature of the aging CNS?

    <p>Loss of myelin</p> Signup and view all the answers

    What is the characteristic of peptidergic vesicles in terms of their response to an increase in [Ca2+]i?

    <p>They are slowed down in their motility</p> Signup and view all the answers

    At what age does the myelination of the CNS profile peak?

    <p>45 years</p> Signup and view all the answers

    What is the role of oligodendrocytes in the human brain?

    <p>To provide central myelination in both white and grey matter</p> Signup and view all the answers

    What is associated with the decrease in the self-renewal capacity of oligodendroglial precursors/NG2 cells?

    <p>Age-dependent myelin deterioration</p> Signup and view all the answers

    What is observed in the astrocytes of 3xTg-AD mice in the pre-symptomatic phase of Alzheimer's disease?

    <p>A decrease in the ATP-evoked, Ca2+-dependent, vesicle mobility</p> Signup and view all the answers

    What can induce cytosolic Ca2+ overload in oligodendrocytes?

    <p>Prolonged or excessive activation of ionotropic receptors</p> Signup and view all the answers

    What is the consequence of oligodendrocyte degeneration and death in the brain?

    <p>A decrease in CNS myelination and the shrinkage of the white matter</p> Signup and view all the answers

    What is the effect of an increase in [Ca2+]i on recycling peptidergic vesicles?

    <p>It slows down their motility</p> Signup and view all the answers

    What is a possible contributor to oligodendroglia death in the context of AD?

    <p>Excitotoxicity mediated by l-glutamate and ATP</p> Signup and view all the answers

    What is the regulatory mechanism that maintains vesicle traffic in astrocytes?

    <p>An increase in [Ca2+]i</p> Signup and view all the answers

    What is a consequence of oligodendrocyte death and myelin destruction in AD?

    <p>White matter degeneration</p> Signup and view all the answers

    What type of receptors do oligodendrocytes express that are permeable to Ca2+?

    <p>Ionotropic receptors</p> Signup and view all the answers

    What is a possible cause of abnormal Ca2+ homeostasis and signalling in oligodendrocytes?

    <p>Alterations in the Ca2+ homeostatic cascades</p> Signup and view all the answers

    What is the possible reason for oligodendrocytes being damaged when exposed to β-amyloid?

    <p>The expression of mutant PS1 increases their sensitivity to l-glutamate toxicity</p> Signup and view all the answers

    What is the effect of injecting β-amyloid into white matter on oligodendrocytes?

    <p>It triggers the death of oligodendrocytes</p> Signup and view all the answers

    What is the role of mutant PS1 in the demyelinating agent cuprizone experiment?

    <p>It increases white matter damage and learning and memory deficits</p> Signup and view all the answers

    What is a possible early marker of Alzheimer's disease?

    <p>Myelin and oligodendrocyte defects</p> Signup and view all the answers

    What is observed in the later phase of 3xTg-AD mice?

    <p>NG2 glia associate themselves with senile plaques and infiltrate the latter with processes</p> Signup and view all the answers

    What is the role of microglial cells in Alzheimer's disease?

    <p>They secrete proinflammatory factors that contribute to neuronal damage</p> Signup and view all the answers

    What is observed in human AD post-mortem tissue?

    <p>A decrease in NG2-positive profiles</p> Signup and view all the answers

    What is the possible consequence of alterations in myelin, oligodendroglia, and oligodendroglial precursors/NG2 cells?

    <p>Pathological remodeling of the connectome and cognitive deficiency</p> Signup and view all the answers

    What is a possible consequence of the loss of microglial phagocytotic function in APP/PS1 mice?

    <p>Facilitated plaque formation</p> Signup and view all the answers

    What triggers the activation of microglia in the AD context?

    <p>All of the above</p> Signup and view all the answers

    What is necessary for the activation of microglia in response to β-amyloid injection?

    <p>P2X7 receptors</p> Signup and view all the answers

    What is observed in the hippocampus of 3xTg-AD mice at 9 months of age?

    <p>Increased density of resting microglia</p> Signup and view all the answers

    What is the effect of a spontaneous loss-of-function mutation in the TLR4 gene on microglial activation induced by Aβ?

    <p>Markedly decreases microglial activation</p> Signup and view all the answers

    At which stage of AD do microglia become activated and recruited to Aβ plaques?

    <p>After the formation of senile plaques</p> Signup and view all the answers

    What is observed in the progression of AD in 3xTg-AD mice?

    <p>Increased density of resting microglia</p> Signup and view all the answers

    What is upregulated in AD animal models and in post-mortem AD brains?

    <p>TLR4 and TLR2 Toll receptors</p> Signup and view all the answers

    Study Notes

    Astrocytes in Alzheimer's Disease

    • Alois Alzheimer observed activated glial cells in close contact with pathologically altered neurons and described glia as a cellular component of the senile plaque.
    • Astrocytes undergo complex morphological changes in animal AD models, including atrophy and astrodegeneration.
    • In the triple transgenic 3xTg-AD mouse, astrocytes in hippocampus, prefrontal and entorhinal cortices demonstrate signs of atrophy and astrodegeneration at the early pre-symptomatic stages.
    • These changes are expressed by a decrease in the GFAP-positive astroglial profiles, decreased somata volume, and a decrease in the number and branching of cell processes.
    • The atrophic changes in astrocytes developed in a particular spatiotemporal pattern, with the earliest signs of atrophy observed in the entorhinal cortex, followed by the prefrontal cortex and hippocampus.

    Vesicular Trafficking and Secretion in Astrocytes Are Altered in AD

    • Vesicular trafficking and secretion in astrocytes are altered in AD, with glutamatergic vesicle motility accelerated by an increase in [Ca2+]i.
    • Peptidergic vesicles and endolysosomes are slowed down by the same increase in [Ca2+]i.
    • Astrocytes from 3xTg-AD mice isolated in the pre-symptomatic phase of the disease exhibit alterations in vesicle traffic, with diminished spontaneous mobility of peptidergic and endolysosomal vesicles.

    Oligodendroglia in Disease

    • Oligodendrocytes provide central myelination in the human brain, which degenerates and dies in various diseases, including AD.
    • Myelin and oligodendrocyte defects in AD occur before the onset of symptoms and may be considered early markers.
    • The loss of myelin is a characteristic feature of the aging CNS, particularly in the cerebral cortex, where decreased myelination and oligodendroglial demise have been identified.

    Oligodendroglia in Alzheimer’s Disease

    • Oligodendroglial cell death and myelin shortages are associated with abnormal Ca2+ homeostasis and signaling.
    • Prolonged or excessive activation of ionotropic receptors, including l-glutamate and P2X receptors, induces cytosolic Ca2+ overload, leading to oligodendrocyte death and myelin destruction.
    • Exposure to β-amyloid damages oligodendrocytes, and mutant PS1 increases their sensitivity to l-glutamate toxicity.

    Microglia in Alzheimer’s Disease

    • Microglial changes, both reactive and degenerative, are an important part of AD progression.
    • Activated microglial cells secrete proinflammatory factors that may contribute to neuronal damage, and loss of microglial function has also been observed.
    • In APP/PS1 mice, appearance of senile plaques coincided with the loss of microglial phagocytotic function, which reduced β-amyloid clearance and facilitated plaque formation.
    • Degeneration of microglia can define neural tissue vulnerability to AD pathology.
    • Activation of microglia in AD may also involve purinergic signaling, TLR4 and TLR2 Toll receptors, and P2X7 receptors.

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