Neuroinflammatory Cytokines – The Common Thread in Alzheimer Pathogenesis
The Common Thread – Glial Activation and Cytokine Expression Familial Alzheimer’s Disease
In a neuropathological analysis of cerebellar tissue from FAD (APP Val717 → Ile: V717F), glial activation was consistently and markedly elevated compared to sporadic AD (SAD). This was correlated with a 25 % decline in Purkinje cell numbers.79
By contrast, Aβ plaque
density – whether extracellular, vascular or perivascular – did not differ between FAD and SAD tissues.
Associations have already been made in AD between increased glial activation and excessive cytokine expression and cell death,70,71,80 similar relationships have been observed in mouse models.81
and Both
human and mouse models, as well as the relationship between cytokines and neurodegeneration, are discussed in a recent review.82
Down’s Syndrome
DS has been suggested as a human model for studying the progression and potential drivers of AD pathogenesis.83
This is because:
• the extra copy of Chr 21 in DS is present in the zygote so that all the players, including the 1.5-fold gene loading and its downstream consequences, are in place at conception; and the innate and, to date unstoppable, outcome is AD.
•
Microglia and astrocytes had previously been found expressing excessive amounts of the systemic immune response-generating cytokine interleukin-1 (IL-1) and astrocyte-derived neuritogenic cytokine S100B, respectively, in the AD brain. Considering the relationships between DS and AD, Griffin et al. set out to assess elements of an innate immune response in the DS brain. They wanted to explore the possibility that changes that are nearly universal in the DS brain would render it a suitable system for studying drivers of AD pathogenesis.
Compared with the brains of non-DS individuals of similar ages, IL-1 and S100B were highly overexpressed in activated glia, even in the brains of foetuses, neonates and children with DS.56
This age distribution is
important; neither Aβ plaques nor neurofibrillary tangles were noted in these brains, nor have these AD neuropathological anomalies been reported in brains from DS individuals of these ages.84,85
Thus, several
studies underscore the importance of these cytokines and precocious development of Aβ plaques and neurofibrillary tangles in DS. These show:
•
• •
•
the increase in IL-1 and S100B expression in DS prior to the detection of either Aβ plaques or neurofibrillary tangles;56,57 the capacity of both IL-186
and S100B to elevate neuronal βAPP;87
the induction of tau phosphorylation through IL-1-induced activation of mitogen-activated protine kinase p-38;65
and
the relation of overexpression of IL-1 and S100B to both Aβ plaque62,88,89
and neurofibrillary tangle63,64 development.57,83
In addition to these DS-related changes that are accompanied by dramatically increased levels of βAPP,90
the resulting overexpression of
the βAPP cleavage fragment βCTF causes endosomal dysfunction.78 Griffin et al. propose that this βCTF expression-dependent increase in endosomal dysfunction is indirectly related to the upregulation of IL-1 by excessive DS-related increases in βAPP and the resulting release of another βAPP cleavage fragments secreted (s)APP. Such sAPP induces glial activation and excessive production and release of IL-191 and
EUROPEAN NEUROLOGICAL REVIEW
A study of a mouse model in which PS-1 and PS-2 functions were eliminated (PSEN1 null mutation with conditional knockout of PSEN2) found:98
• substantial glial activation; • •
neuronal loss in the cortex and hippocampus; cortical and hippocampal atrophy; and
• tau hyperphosphorylation with tangle-like intraneuronal inclusions.
All of this occurred with no additional production of Aβ. The activation of glia and the accompanying increase in cytokines, such as S100B
91
Crossing another APP-transgenic mouse (Tg2576) with transgenic mice overexpressing S100B (TghuS100B) exaggerated the glial activation and increased expression of S100B above the level in the TghuS100B mice. It also increased expression of IL-1β, IL-6 and tumour necrosis factor alpha (TNF-α) above the expression level in Tg2576 mice.34
The increase in glial activation and overexpression of these cytokines was an early phenomenon that foreshadowed an increase in plaque density and Aβ levels.34
Compared with littermate-controls (non-transgenic mice), V717F mice had elevated numbers of activated astrocytes overexpressing S100B as early as two months of age, while the first Aβ plaques were not found until eight months.96
The tissue levels of S100B mRNA and
protein were elevated at each month from the second to eighth and from that time were correlated with Aβ load in these mice.96
In
addition, the expression of the IL-1β-converting enzyme is greatly increased in these mice, again before plaque formation, and was closely correlated with neuronal DNA damage and cell loss. This is consistent with the idea that increases in active IL-1β contribute to Aβ plaque formation and to neuronal degeneration in mouse models of AD and by analogy to AD.70
Accompanying this astrocyte activation in
V717F transgenic mice, there is microglial activation with overexpression of IL-1 and other inflammation parameters, again prior to Aβ plaque deposition.97
Animal Models
The creation of mouse models of FAD through transgenesis with mutations or deletions of APP, PSEN1 and PSEN2 have greatly aided in the understanding of AD pathogenesis.
Glial activation is a prominent feature in these models from the first FAD-mutant APP (V717F) transgenic mouse model.20
In more recent
studies, astrocyte activation in V717F transgenic mice was shown to be accompanied by microglial activation months before the appearance of Aβ plaques in these animals.
bCTF, which results in endosomal dysfunction and leads to the build-up of unwanted proteins. This induces glial activation and excessive production and release of IL-191
and βCTF, which results in endosomal dysfunction and leads to the buildup of unwanted proteins.92
These events may create another opportunity for progression through positive feed-forward. The APP intracellular domain, produced by γ-secretase cleavage of βCTF, is capable of promoting AD-related symptoms – including tau pathology and inhibition of neurogenesis – in a manner sensitive to NSAIDs.93
This may be
related to the expanding evidence for an inhibition of neurogenesis by IL-1.94,95
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