Thesis

Depression-like behaviour in a mouse model of Alzheimer’s disease : a reverse translational study

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Awarding institution
  • University of Strathclyde
Date of award
  • 2026
Thesis identifier
  • T17618
Person Identifier (Local)
  • 202270899
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Abstract
  • Alzheimer’s disease (AD) represents a major global health burden, withprevalence continuing to rise and current treatments offering limited efficacy.Growing evidence highlights neuroinflammation as a key driver of ADprogression, with activated microglia and reactive astrocytes contributing toand accelerating AD pathology. Similarly, major depressive disorder (MDD) ischaracterised by enhanced neuroinflammation, including elevated levels ofpro-inflammatory cytokines, and is recognised as a risk factor for AD.Furthermore, patients experiencing both MDD and AD show accelerateddisease progression and a worse prognosis, suggesting that MDD could actas an early biomarker or intervention target for AD therapeutics. Recentfindings demonstrate that protease-activated receptor 2 (PAR2) activationinduced behavioural changes associated with depression-like behaviour andcytokine release in vivo. Based on this, we hypothesised that PAR2 activationvia activator AC264613, as well as LPS-induced inflammation, would elicitdepression-like behaviour and exacerbate neuroinflammation and amyloidbeta (A?) 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-1i.p.)or lipopolysaccharide (LPS: 0.5 mg kg-1i.p.) and locomotor activity, anhedoniaand apathy were investigated 2h and 24h post-injection. Both AC and LPSinduced behavioural changes associated with depression-like behaviour,demonstrated by reduced locomotor activity, sucrose preference, andgrooming behaviour, which were exacerbated under environmental stress.Immunohistochemistry revealed that AC and LPS induced transientimmunomodulatory effects, reducing astrocyte reactivity and A? plaquedeposition at 3 weeks post-injection in female 5xFAD+/- mice but had no effecton activated or phagocytic microglia. Both AC and LPS altered pro- and antiinflammatory cytokine release in 5xFAD-/- mice, while AC had minimal effectsin 5xFAD+/- mice. In addition, PAR2 activation increased blood brain barrier(BBB) permeability, whereas PAR2 inhibition maintained BBB integrity andprevented AC induced disruption.Overall, this study expands our knowledge on the neuroprotective andimmunomodulatory properties of PAR2, highlighting its potential as atherapeutic target for modulating neuroinflammation, A? plaque deposition andBBB integrity, offering promising new avenues for AD treatments.
Advisor / supervisor
  • Bushell, Trevor
  • Sakata, Shuzo
Resource Type
DOI
Date Created
  • 2025
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