Alzheimer’s disease is an aging related disorder of the mind, accountable for 60-80 percent of all cases of dementia. With its insidious progression and the decline of cognitive abilities, this disease is a major challenge for our society as a whole. This is because of the growing proportion of people living to advanced age and our current lack of capacity to prevent or even give effective symptomatic treatments to the disorder. At the advanced stages of the disease the patient is more or less completely dependent upon help from caregivers and family placing a huge stress on both society and the patient’s next of kin.
Alzheimer’s disease is characterized by two cardinal pathological lesions. First, the senile plaques, consisting of β-amyloid, and second, the neurofibrillary tangles consisting of Tau. While most Alzheimer’s disease cases have an unknown etiology there are cases of familial Alzheimer’s disease, where a single mutated gene gives rise to the disease, typically with an early onset of symptoms. These disease related mutations all point to a critical role of the peptide β-amyloid and the processing of its precursor protein, the amyloid precursor protein (APP). While β-amyloid and APP have been studied extensively for almost three decades, we still require more knowledge of their normal roles in the brain.
Multiple lines of evidence implicates synapses as early and critical sites of β-
amyloid and APP function and dysfunction. The loss of synaptic terminals remains
the best pathological correlate of the cognitive decline in Alzheimer’s disease.
In this thesis, on the nature of β-amyloid, we set out to investigate some of the roles β-amyloid and APP play at synapses, both in normal physiology and disease. We found that depletion of APP leads to alterations in synaptic composition and
neuronal morphology. We showed that β-amyloid aggregates even before the
appearance of plaques and that this concurs with the disappearance of a 20 kD
putative tetramer in brains of Alzheimer’s disease model transgenic mice.
Moreover, we investigated the effects of two familial Alzheimer’s disease mutations on synaptic proteins in hippocampal spheroids generated from induced pluripotent stem cells (iPSCs) from patients and healthy gender matched controls. We found that many of the changes between Alzheimer’s disease hippocampal spheroids and normal samples were in synaptic proteins. The final study focuses on the effects of β-amyloid on neuronal hyper-excitability, an increasingly highlighted early feature in Alzheimer’s disease that is also recapitulated in animal models of the disease. We describe specific effects of β-amyloid on cortical CaMKII positive neurons, increasing both firing frequency and amplitude of these cells, highlighting that β-amyloid targeting of CaMKII positive synapses might contribute to the hyperexcitability that is increasingly viewed as an early feature in Alzheimer’s disease.
Taken together this work describes and attempts to explain important roles that β-amyloid and APP play at synapses, with implications both for health and disease.
- Institutionen för experimentell medicinsk vetenskap
- Keppler Gouras, Gunnar, handledare
- Hansson, Oskar, Biträdande handledare
|Tilldelningsdatum||2019 dec. 12|
|Status||Published - 2019|
Place: Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
Name: Kins, Stefan
Affiliation: Technische Universität Kaiserslautern, Kaiserslautern, Germany
- Medicin och hälsovetenskap