There is increasing evidence that neuro-inflammation drives disease progression in many neurodegenerative conditions. Amyotrophic lateral sclerosis (ALS) is a debilitating, late onset neurodegenerative disorder that is characterized by the progressive death of upper and α-motor neurons within the central nervous system (CNS). Components of the innate immune complement system have been implicated in the pathogenesis of ALS. Within the complement signalling cascade C3a and C5a are regarded as potent inflammatory and immunomodulatory peptides with various biological functions. In the CNS their functions include chemotaxis and proliferation of microglia and astrocytes; generation of superoxide radicals; and induction of pro-inflammatory cytokine synthesis – all thought to be achieved via their main signalling receptors C3aR and CD88. Some of these functions have been observed in neurodegenerative disease, suggesting that these complement factors may play a role in ALS pathogenesis. However a comprehensive examination of complement expression and function of C3aR and CD88 in this disease has not been performed.The initial aim of this thesis was to determine the expression of complement components (C1qB, C4, factor B, C3/C3b, C5, CD88 and C3aR) and regulators (CD55 and CD59a) in the lumbar spinal cord of the transgenic hSOD1G93A mouse model of ALS. This was conducted during distinct disease stages, which were defined in this thesis. We found several early complement factors increased as disease progressed, whilst complement regulators decreased; suggesting overall increased complement activation through the classical or alternative pathways in hSOD1G93A mice. CD88 and C3aR was also increased during disease progression, with immunolocalization demonstrating expression on motor neurons and increasing expression of CD88 on microglia and increasing expression of C3aR on astrocytes surrounding the regions of motor neuron death.Our previous studies have demonstrated that hSOD1G93A rats treated with the selective CD88 antagonist PMX205 had reduced gliosis and improvements in behavioural deficits, consistent with reduced neuropathology; suggesting CD88 has a pathogenic function in ALS. However, the contribution of C3aR to disease progression in ALS is still unknown. This thesis therefore next aimed to confirm the function of CD88, and determine the function of C3aR, in the disease progression of ALS in hSOD1G93A mice. The function of CD88 signalling was investigated using two different approaches (pharmacological and genetic). Inhibition of CD88 using PMX205 (pharmacological approach) or hSOD1G93A mice lacking CD88 (genetic approach) showed similarly extended survival when compared to vehicle and hSOD1G93A mice. There was also a reduction in microglia, monocytes and cytokines (TNFα and IL-1β) transcripts in the spinal cord at the end-stage of disease. Taken together these results indicate that inhibition of CD88 significantly attenuates disease progression potentially by reducing microglia/monocyte activation and generation of proinflammatory cytokines, which all have an important role in motor neuron death that contributes to pathology in the hSOD1G93A mice.Due to a lack of a selective and brain permeable C3aR antagonist, the function of C3aR signalling was investigated by using hSOD1G93A mice lacking C3aR (hSOD1G93A x C3aR-/-) and comparing survival with hSOD1G93A mice. By contrast with CD88, hSOD1G93A x C3aR-/- mice showed significantly reduced survival relative to hSOD1G93A mice and showed worsened behavioural deficits compared to hSOD1G93A mice. There were also increased astrocyte and microglia transcripts but no change in cytokines (TNFα and IL-1β) transcript levels in the spinal cord at endstage of disease. Taken together these results indicate that inhibition of C3aR significantly exacerbates disease progression potentially by increasing astrocytes and microglia activation, independent to inflammatory cytokines. This finding also opens a new window of opportunity to target C3a-C3aR signalling in astrocytes using selective agonists, to potentially slow ALS disease progression.In summary, these results indicate that there is dysregulation of the complement system in the disease progression in a widely used ALS transgenic model. Complement peptides C3a and C5a generated during complement activation and their receptors C3aR and CD88 have two opposing roles in the progression of ALS in the hSOD1G93A mouse. Hence therapeutic modulation of complement activation in ALS should be targeted towards downstream C5a inhibition, in order to avoid blocking any endogenous protective effects of upstream factors such as C3a in ALS progression.