Neuron-specific alterations in signal transduction pathways associated with Alzheimer's disease

The hallmarks of sporadic Alzheimer's disease (AD) are extracellular amyloid deposits, intracellular neurofibrillary tangles (NFTs), and neuronal death. Hyperphosphorylation of tau is a key factor in the generation of NFTs. Mitogen activated protein kinase 1 (MAPK1) and protein kinase C beta (PRKCB) are thought to play a role in hyperphosphorylation, and PRCKB is thought to be involved in hypoxic stress and vascular dysfunction, and to trigger MAPK phosphorylation pathways. We performed single-cell analyses of neurons with different vulnerabilities to AD-related changes. Using quantitative PCR (qPCR), we measured the levels of MAPK1 and PRKCB transcript in CA1 (high vulnerability), CA2 pyramidal cells from the hippocampus, granule cells from the cerebellum (low vulnerability), and neurons from the brain stem (nucleus tractus spinalis nervi trigemini, characterized by early neurophysiological deficits) at progressive Braak stages compared to age-matched controls. The highly vulnerable CA1 pyramidal neurons were characterized by age- and disease-unrelated increases in PRCKB levels and by age- and disease-related increases in MAPK1 levels. In contrast, low PRKCB levels were found in CA2 pyramidal neurons, and MAPK1 levels were elevated in controls and intermediate AD stages. Both PRKCB and MAPK1 were increased in the late AD stages. MAPK1 and PRKCB levels were low in the brainstem and cerebellum. We propose that alterations in the expression of these two genes occur early in the pathogenesis of AD in a region-specific manner. In addition, multiple signal transduction pathways need to be affected to result in AD instead of physiological aging

Neuron-specific mitochondrial DNA deletion levels in sporadic Alzheimer´s disease

Oxidative stress is implicated in the pathogenesis of neurodegenerative diseases, including sporadic Alzheimer´s disease (AD). Mitochondrial DNA (mtDNA) deletions are markers of oxidative damage and increase with age. To unravel the impact of mtDNA damage on AD development, we analyzed mtDNA deletion levels in diverse neuronal cell types of four brain regions (hippocampal CA1 and CA2 regions, nucleus tractus spinalis nervi trigemini, and the cerebellum) that exhibit differing levels of vulnerability to AD related changes at progressive Braak stages compared with age-matched controls. Neurons from these four brain regions were collected using laser microdissection, and analyzed using quantitative polymerase chain reaction (qPCR). Although, no correlation between mtDNA deletion levels and AD progression were found, the data revealed regional and cell type specific selective vulnerability towards mtDNA deletion levels. In conclusion, unexpected results were obtained as granule cells from the cerebellum and neurons from the nucleus tractus spinalis nervi trigemini of the brain stem displayed significant higher mtDNA deletion levels than pyramidal cells from hippocampal CA1 and CA2 region in age and AD