The CNS injury response and its relationship to Alzheimer's disease

Regeneration in the adult mammalian CNS is a contentious issue. From the early studies of Ramon y Cajal (1928), it has been accepted that CNS neurons do not regenerate in the same fashion as neurons residing within the PNS. However, this philosophy has held in the extreme, whereby all reactive neuronal changes following injury were considered to be regressive and all sprouting attempts, abortive. As a consequence, the innate regenerative potential of CNS neurons has received little recognition. Recent studies have demonstrated the ability of some central nerve cell populations to mount robust and sustained regenerative responses following injury, including the extension of axonal sprouts, appropriate directional growth of processes and the formation of synaptic connections. However, many of these studies have dealt with relatively simple fibre tracts, mild injuries and involved the introduction of growth-enhancing factors or materials. A criticism of investigations with limited and controlled injury conditions may be the inability to translate these findings to the extensive damage of complicated fibre systems, characteristic of many human traumatic brain injuries. furthermore, the confounding effects of the CNS environment including a compromised blood brain barrier, intense glial reaction and myelin associated factors are considered important barriers to successful regeneration following CNS injury. The central purpose of this thesis was to revisit CNS regeneration, usrng immunohistochemical and ultrastructural methods to investigate the wound healing response in an in vivo animal model of acute cortical grey and white matter injury. It further sought to examine the role of cytoskeletal proteins, particularly the neurofilament (NF) triplet, in the reaction of axons to injury and subsequent sequence of cellular changes involved in neuropil restoration. A final objective was to determine the existence of innate regenerative potential in adult central neurons in the presence of factors which are considered to be extremely inhibitory to neurite outgrowth; including CNS myelin, glial scarring and a compromised blood brain barrier. Studies of CNS injury have also provided important information regarding the biological mechanisms underlying certain neurodegenerative conditions, such as Alzheimer's disease (AD). Despite its characterisation over a century ago, the aetiology of AD remains obscured by unknowns. These include the precise relationship between the two main pathological hallmarks, the 13-amyloid plaque and neurofibrillary tangle, the method by which 13-amyloid inflicts its damage on the surrounding neuropil and the biological mechanism underlying neurodegeneration. One aspect of the disease which has been firmly established, however, is the select vulnerability of large NF-positive pyramidal cells to degenerate in this condition. NFs have been shown to undergo specific alterations within cell perikarya and processes in the early stages of AD and, significantly, some aspects of this early cytoskeletal pathology are recapitulated within nerve cells following physical injury. A second major aim of this thesis was to investigate the possibility of a link between physical injury to neurons and the precise cellular changes underlying neurodegeneration in AD by focusing on the role of cytoskeletal changes in both conditions. When the experimental injury response was assessed ave~ a time course, a distinct stereotypy was observed in the process of wound healing and resolution of neuronal pathology. This involved an ordered sequence of morphological, neurochemical and ultrastructural changes to neurites, including specific alterations to neurofilament triplet proteins, as well as intimate associations between reactive processes and glial populations. Furthermore, evidence of reactive sprouting was observed within both grey and white matter axons, supporting the existence of innate regenerative potential within CNS neurons under the inhibitory influences of reactive glia and heavy myelination. A number of similarities were also demonstrated between the response of damaged cortical neurites to acute injury and the early neuritic pathology of AD associated with plaque formation. Characterisation of the stereotypical reaction of nerve cells to experimental physical injury, as well as the existence of innate regenerative potential, provides insight into the nature of the CNS regenerative response, an important understanding for the development of therapeutic strategies aimed at improving regeneration. Furthermore, the establishment of a link between the neuronal response to physical injury and the neuropathology of AD will enhance the value of this characterisation, whereby intervention in the stereotypical response to injury may be used to halt or slow the progression of degenerative changes in AD.