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, 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.
Advisor / supervisor
  • Bushell, Trevor
  • Sakata, Shuzo
Resource Type
DOI
Date Created
  • 2025
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