Pathological Alterations Induced by intraneuronal in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is pathologically characterized by the deposition of amyloid beta (Aβ) and neurofibrillary tangles (NFT) consisting of hyperphosphorylated tau protein. Since familial mutations in proteins involved in the Aβ generating cascade inevitably lead to AD, the deposition of Aβ is widely believed to be the underlying pathological mechanism of AD. In contrast, mutations in tau lead to frontotemporal dementia. The amyloid hypothesis states that the accumulation of Aβ42 is the underlying cause of AD driving neuron and synapse impairment and loss, eventually leading to behavioral deficits. For many years, the focus of the Aβ hypothesis has been the extracellular deposition of Aβ plaques; however numerous mouse models have been generated based on the familial AD mutations successfully modeling the deposition of Aβ plaques, but with little or no behavioral deficits and only seldom showing a loss of neurons. Furthermore, Aβ plaque deposition does not correlate well with cognitive decline in AD patients and can be found in non-demented controls as well as in AD patients. Recently, a modification of the amyloid hypothesis has been introduced suggesting that intraneuronal accumulation of Aβ rather than extracellular Aβ plaque deposition may be an early pathological hallmark of AD initiating pathological events. However, the presence of intraneuronal Aβ in the human AD brain is currently under debate. The present thesis investigates the presence of intraneuronal Aβ in human AD brain tissue and studies the role of intraneuronal Aβ versus plaques in transgenic mouse models of AD focusing on neuron loss, fiber pathology, and functional deficits concerning immediate early gene (IEG) regulation. Concerning pathological alterations, the present thesis corroborates the intraneuronal Aβ hypothesis, supporting the view of intraneuronal Aβ as an early pathological initiator and showing strong implications for intraneuronal Aβ in the generation of large plaque-independent axonal fiber pathology and neuronal loss. In contrast, plaques are found likely to cause functional disturbances such as deficits in the induction of IEGs upon neuronal activity, but seem not to be involved in the loss of neurons. Optimization of the immunohistochemical staining method for the detection of intraneuronal Aβ peptides provided a strong and robust staining of intraneuronal N-terminal Aβ peptides as well as fibrillar oligomeric Aβ and Aβ fibrils in neurons of the hippocampal formation of AD brain tissue. Finally, a highly significant correlation was identified between the accumulation of intraneuronal N-terminal Aβ peptides and the well-recognized AD risk factor of having one ApoE4 allele, emphasizing an important role of intraneuronal Aβ in AD pathology.