Neuroinflammation in Alzheimer’s Disease - Geesdorf Flashcards
What are A-beta plaques?
extracellular deposits of A-beta derived from the beta-amyloid precursor protein (APP). They lead to Tau phosphorilation + aggregation.
What are NFT’s?
intracellular hyperphosphorilated tau accumulation. They lead to synaptic damage and then dementia.
What is the amyloid hypothesis?
Beta secretase cleaves alpha-beta protein leading to the aggregation of miscleaved A-beta protein and the formation of plaques. Can be made up of A-beta monomers, A-beta oligomers, A-beta protofibrils, and A-beta fibrils leading to plaques.
What is the Tau hypothesis?
Tau monomers mixed with Tau-Preformed-Fibrils (PFF’s), lead to Tau fibrils, which morm paired helical filaments and neurofibrillary tangles. This causes neuronal cell death, and contributes to dementia.
Does neuroinflammation occur in AD?
The presence of Aβ (as well as other pathological protein deposits, alterations in the CNS, systemic or local inflammation, and mutations in genes encoding innate immune molecules) can ‘prime’ microglial cells; that is, Aβ makes these cells susceptible to a secondary stimulus and/or promotes their activation. Priming results in various functional microglia phenotypes (indicated by different colours), presumably accompanied with no or only minor morphological alterations and/or no (major) cell-surface marker differences. In AD, Aβ sustains chronic activation of primed microglia (due to the peptide’s accumulation), which results in a constant production of inflammatory cytokines and chemokines by these cells; in turn, the cytokines and chemokines maintain activation of the primed cells. This process results in a vicious circle, which ultimately impairs microglia (although this impairment is reversible for some time); moreover, it affects surrounding CNS resident cells (astrocytes, oligodendrocytes and neurons), possibly aggravating tau pathology (denoted by the dashed line and a question mark), and finally causing neurodegeneration and neuron loss. If these processes perpetuate over a prolonged period, it forces microglia into a senescent, ‘burn-out’-like (dystrophic) phenotype, which is thought to be irreversible
How does AD differ from traditional neuroinflammatory diseases?
The tissue invasion of blood-derived leukocytes of the adaptive immune system (T and B lymphocytes) whcih is a prominent feature of MS and encephalities. Different from other neurodegenerative diseases because the inflammatory reaction observed in AD is driven primarily by CNS-resident immune cells (microglia, perivascular myeloid cells).
What is the difference between neurodegenerative disease that is innate immune system-driven, and neuroinflammatory disease that is adaptive immune system-driven?
Neuroinflammation in various CNS disorders can be differentiated by the nature of inflammation; that is, diseases may be classified according to if CNS-resident and/or potentially blood-derived innate immune cells are the major pathogenic component (as in neurodegenerative diseases such as Alzheimer disease) (a), or if predominantly adaptive immune cells (B and T lymphocytes) drive the pathological process (as seen in encephalitides or multiple sclerosis (MS)) (b). The main contribution — apart from astrocytes — of the innate immune system in neurodegenerative diseases occurs within the CNS through resident microglia and perivascular macrophages, whereas the involvement of other blood-derived myeloid cells such as dendritic cells and monocytes appear to have no major impact on the course of neurodegeneration. Whether — and if so, to what extent — monocytes are recruited from the periphery to the CNS in the course of the disease is not entirely clear (denoted by the dashed arrow and a question mark) (a). Traditionally defined neuroinflammatory diseases such as MS are primarily driven by cells of the adaptive immune system such as T and B lymphocytes; various subtypes of myeloid cells have, however, also important pathogenic implications; blood-derived monocytes represent in fact the most numerous infiltrate into the CNS where they transform into monocyte-derived inflammatory phagocytes (macrophages or dendritic cells) and are thought to mediate much of the tissue damage observed (denoted by the thick arrow). As in neurodegenerative diseases, astrocytes and microglia also react to pathology, although it is not clear whether the type of response is similar to what happens in neurodegeneration (b).
Can neuroinflammation influence A-beta aggregation?
Possibly, maternal immune activation with Poly I:C could lead to immune system activation leads to neuroinflammation leads to A-beta plaque aggregation which means the same could potentially happen with an infection.
Where does neuroinflammation come from?
1) CNS intrinsic factors: traumatic brain injury, facilitates the development of AD pathology
2) Systemic influences:
chronic diseases (ie. psoriasis), leads to an increased risk of developing dementia (due to a “worse” lifestyle or simply because of biological diversity)
What are the pro-inflammatory cytokines?
IL-1b
TNF-alpha
IL-12
IL-23
IL-6
What are the anti-inflammatory cytokines?
IL-10
Il-4
TGF-beta
IL-13
What are the upregulated cytokines in AD mouse models/AD patients?
IL-1
IL-6
GM-CSF
IL-12
TNF-alpha
IL-10
What is the downregulated cytokine in AD?
TGF-beta
How does neuroinflammation in AD possibly develop?
Infections?MIA/chronic disease leads to immune system activation which leads to neuroinflammation contributing to the aggregation of miscleaved A-beta protein and formation of plaques leading to neurofibrillary tangles which ultimately leads to neuronal loss.
Which cell types are responsible for AD development and progression?
Miroglia, Myeloid cells other than resident microglia, astrocytes and other CNS cells.
What are microglia?
CNS-resident myeloid cells of embryonic haematopoietic origin (derived from the yolk sac), they survey the brain for pathogens, they support CNS homeostasis, they sense danger signals, such as protein aggregates in AD, and respond to changes in neuronal health by adapting through a set of morphological and functional changes.
How do microglia promote neuroinflammation?
A-beta monomers with a receptor mediated interaction - relatively non-toxic may prime inflammatory signalling
A-beta oligomers with a non-receptor mediated interaction - toxic to microglia, driving them to a dystrophic phenotype which reduces phagocytic capacity.
Protofibrils with receptor-mediated interaction elicits cytokine production, and may enhance oligomer toxicity to microglia, resulting in dystrophic phenotype.
Fibrils with receptor mediated interaction elicit cytokine production and may activate inflammasomes.
How is A-beta cleared by microglia?
In vitro - through receptor mediated phagocytosis and degradation
In vivo - unclear whether microglia themselves phagocytose A-beta fibrils in a pathophysiological AD setting.
Soluble A-beta species via extracellular processes such as neprilysin and insulin-degrading enzyme (IDE)
What is the effect of A-beta on microglia?
- Decreased phagocytosis of beads in vitro
- Production of inflammatory cytokines
- Amoeboid morphology of microglia = “toxic microglia”
- Reduced capacity to extend processes towards a tissue lesion
- Less A-beta binding receptor expression: elimination of protective properties.
-> transient depletion of microglia has no impact on A-beta burden in an animal model of AD
What is the phagocytic capacity of microglia in AD?
Hypothesis: chronic activation of microglia leads to the chronic production of cytokines, the decreased phagocytic capacity, and the decreased ability to maintain myelin integrity.
However, IL-10 upregulates phagocytosis in monocytes, IL-4 impairs phagocytosis in macrophages, TNF-alpha inhibits phagocytosis in macrophages and many immune factors have dual roles (they can either promote or ameliorate pathology of different diseases, settings and doses).
What are the myeloid cells other than resident microglia?
Meningeal and choroid plexus macrophages, perivascular macrophages which physiologically remove A-beta and protect from amyloid pathology, their role in AD is still discussed, ad Border-associated macrophages (BAMs)
What are astrocytes?
CNS-resident cells of neuroectodermal origin, they respond to pathological stimuli through reactive gliosis, they form the blood-brain barrier and synapses (tripartite synapse), they also regulate glutamate, neurotransmitter, support oligodendrocytes and thus myelination = neuronal survival.
What is the role of astrocytes in AD?
Their activation occurs early in the course of pathogenesis, they undergo atrophy that precedes the A-beta plaque-related astrogliosis, deficient glutamate transmission leads to cognitive impairment, and contribute to a leaky blood brain barrier (BBB)
How do astrocytes promote neuroinflammation?
a neuroinflammatory insult to resting microglia causes them to become inflammatory microglia that target a “resting astrocyte” turning it into an A1 reactive astrocyte probably secreting A1 molecules leading to increased toxicity, reduction in OPC differentiation, OPC migration, and neuron function.
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