Alzheimer’s disease (AD) represents a major global health burden, with
prevalence continuing to rise and current treatments offering limited efficacy.
Growing evidence highlights neuroinflammation as a key driver of AD
progression, with activated microglia and reactive astrocytes contributing to
and accelerating AD pathology. Similarly, major depressive disorder (MDD) is
characterised by enhanced neuroinflammation, including elevated levels of
pro-inflammatory cytokines, and is recognised as a risk factor for AD.
Furthermore, patients experiencing both MDD and AD show accelerated
disease progression and a worse prognosis, suggesting that MDD could act
as an early biomarker or intervention target for AD therapeutics. Recent
findings demonstrate that protease-activated receptor 2 (PAR2) activation
induced behavioural changes associated with depression-like behaviour and
cytokine release in vivo. Based on this, we hypothesised that PAR2 activation
via activator AC264613, as well as LPS-induced inflammation, would elicit
depression-like behaviour and exacerbate neuroinflammation and amyloidbeta (Aβ) deposition in the 5xFAD mouse model.
10-12-week-old mice (5xFAD-/- and 5xFAD+/-
littermates and C57BL6/J wildtypes) were injected with either vehicle (i.p.), AC264613 (AC: 100 mg kg-1
i.p.)
or lipopolysaccharide (LPS: 0.5 mg kg-1
i.p.) and locomotor activity, anhedonia
and apathy were investigated 2h and 24h post-injection. Both AC and LPS
induced behavioural changes associated with depression-like behaviour,
demonstrated by reduced locomotor activity, sucrose preference, and
grooming behaviour, which were exacerbated under environmental stress.
Immunohistochemistry revealed that AC and LPS induced transient
immunomodulatory effects, reducing astrocyte reactivity and Aβ plaque
deposition at 3 weeks post-injection in female 5xFAD+/- mice but had no effect
on activated or phagocytic microglia. Both AC and LPS altered pro- and antiinflammatory cytokine release in 5xFAD-/- mice, while AC had minimal effects
in 5xFAD+/- mice. In addition, PAR2 activation increased blood brain barrier
(BBB) permeability, whereas PAR2 inhibition maintained BBB integrity and
prevented AC induced disruption.
Overall, this study expands our knowledge on the neuroprotective and
immunomodulatory properties of PAR2, highlighting its potential as a
therapeutic target for modulating neuroinflammation, Aβ plaque deposition and
BBB integrity, offering promising new avenues for AD treatments.
| Date of Award | 10 Feb 2026 |
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| Original language | English |
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| Awarding Institution | - University Of Strathclyde
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| Sponsors | University of Strathclyde |
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| Supervisor | Trevor Bushell (Supervisor) & Shuzo Sakata (Supervisor) |
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