Supervisors info:
Ισιδώρα Παπασιδέρη, Καθηγήτρια Βιολογίας, Τομέας Βιολογίας Κυττάρου & Ανάπτυξης
Δημήτρης Στραβοπόδης, Αναπληρωτής Καθηγητής Βιολογίας, Τομέας Βιολογίας Κυττάρου & Ανάπτυξης (Επιβλέπων)
Σπύρος Γεωργόπουλος, Ερευνητής Β’ ΙΙΒΕΑΑ, Εργαστήριο Κυτταρικής Νευροβιολογίας (Επιστημονικός Υπεύθυνος)
Summary:
Alzheimer's disease is a neurodegenerative disease that affects a significant number of
patients worldwide and can be categorized in two different subtypes: Familial and Sporadic
Alzheimer’s Disease. One of the major symptoms of the disease is the gradual memory and
cognitive skills impairment resulting in difficult circumstances for patients and their families.
Regarding the neuropathological features of the disease, the formation and deposition of betaamyloid plaques and neuro-fibrous bundles on the brain are observed.
Ongoing research on Alzheimer's disease is constantly producing new data highlighting that
inflammation and its mediators play an active role in the pathogenesis of the disease. As a
result, research has also shifted to investigate the role of TNF-α, a pleiotropic proinflammatory cytokine; TNF-α acts through its two receptors, TNFRI and TNFRII, and its
expression in the brain, is mainly observed in the microglia and astrocytes. However, the
known data, so far, on the role of TNF-α are quite ambiguous, since there are data supporting its beneficial and protective effect, while others demonstrate its neurotoxic effect.
In the present study, we examined the effect of overexpression of TNF-α on the amyloid
phenotype in transgenic mouse-models of Alzheimer's disease. Thus, the 5XFAD model of
Alzheimer's disease, carrying 5 known familial variants of the disease, was mated with
TNFΔARE / + mice that overexpress TNF-α, after deletion of ARE regions.
The study was performed on 4-month-old female mice, since a sufficient number of amyloid
plaques is being observed at this time point. The main finding of the present study was the
significant reduction of amyloid plaques in both cortex and hippocampus in 5XFADTNFΔARE/+ mice, whereas levels of degradation enzymes (BACE1, ADAM10) of APP
protein were not affected; moreover TACE, the enzyme that converts membrane-bound TNF-α into soluble TNF-α, was not affected either.
At the same time, an increase in the levels of Iba1, an indicator of microglial cells, was
observed, while levels of GFAP, an indicator of astrocytes, were not affected. Finally,
elevated levels of TNF-α in the serum was observed, while its levels in brain protein extract
remained stable.
Therefore, we concluded that overexpression of (mu)TNF-α leads to an increase on TNF-α
levels in the periphery, and this increase appears to affect the amyloid phenotype of the brain by decreasing amyloid plaques, while activating the immune system of the brain, and
especially the microglial cells, without affecting APP’s degradation enzymes.
Keywords:
Alzheimer's disease, AD, inflammation, transgenic mouse, β-amyloid peptide, Aβ, TNF-α
