Plasticity in the Human Alzheimer’s Disease Brain

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the leading cause of dementia. The characteristic symptoms of AD result from cortical atrophy that follows the spread of β-amyloid and tau aggregates through the brain. The earliest regions affected in AD are areas of high plasticity such as the hippocampus and entorhinal cortex, where new neurons are born (neurogenesis) and mature cells undergo structural and synaptic modification throughout life. It is thought that impaired plasticity in these regions may contribute to cortical atrophy and development of symptoms. There is currently only a partial understanding of the mechanisms that contribute to human brain plasticity and how they are affected in AD. This thesis examined two mechanisms of plasticity in post-mortem human brain tissue from control and AD cases using immunohistochemistry. The first section of the thesis examined neuronal proliferation in the sub-granular zone (SGZ) and sub-ventricular zone (SVZ) neurogenic niches using cell counting methods on full tissue sections and tissue microarrays. The results of this quantification revealed that the number of proliferating cells in the SGZ and SVZ was unaltered in AD cases. However, there was an increase in the number of PSA-NCAM+ immature granule cells in the SGZ. This work indicates that neuronal proliferation is unaltered in AD, but changes may occur in the structural maturation of progenitor cells. The second section of this thesis examined the distribution of PSA-NCAM expression in the human brain. PSA-NCAM is a membrane bound glycoprotein that mediates cell migration and structural plasticity through the regulation of cell-cell adhesion. PSA-NCAM distribution and function is commonly described in the SGZ and SVZ of the adult human brain, but there is limited evidence of its expression outside these regions. In this study, PSA-NCAM was found to be widely expressed throughout the adult human brain. Furthermore, PSA-NCAM+ cells were found in the caudate nucleus and cerebellum, two structures considered devoid of PSA-NCAM in the rodent brain. PSA-NCAM distribution was conserved throughout the AD brain except the entorhinal cortex, where PSA-NCAM staining load was significantly reduced and inversely correlated with tau load. These results indicate that PSA-NCAM-mediated plasticity is an important mechanism that is reduced in a region of the AD brain severely affected by aggregate pathology and associated with memory symptoms. Further characterisation of PSA-NCAM+ cells throughout the brain revealed an interneuron phenotype was predominant. An investigation of entorhinal cortex PSA-NCAM+ interneuron populations showed these cells were not selectively preserved or degenerated in AD. Overall this thesis has contributed key insights into neuronal proliferation and PSA-NCAM-mediated plasticity in the control and AD human brain.