The role of astrocytic amyloid precursor protein in the regulation of synaptic plasticity

Crux, Sophie (2018): The role of astrocytic amyloid precursor protein in the regulation of synaptic plasticity. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

Alzheimer's disease (AD) is the most common form of dementia affecting 47 million people worldwide and rising numbers are predicted for the future, as increasing life expectancy denotes increased risk of developing AD. The disease constitutes an enormous burden for our society. Despite numerous therapeutical approaches, a cure for AD has not been found yet. One hallmark of AD is the accumulation of amyloid beta (Abeta) which is intensively studied and widely considered as molecular explanation for the synaptic pathology in AD. Today's therapeutic strategies target AD symptoms and first mechanistic approaches, including interference with Abeta production, are failing in clinical trials. Hence, it remains of utmost importance to further understand the fundamental biology of AD-related physiology in order to develop successful therapeutic strategies. Abeta is a cleavage product of the amyloid precursor protein (APP). However, the physiological functions of APP remain less well understood and previous investigations have been mainly confined to neurons. Neuronal information flow between pre- and postsynapse is strongly dependent on the adjacent astrocytes that are involved in synaptic information processing, transmission and plasticity. Synaptic plasticity is considered to be the underlying mechanisms of learning and memory. In the present work, the physiological role of APP was investigated both in synaptic plasticity and associated astrocytes in a constitutive and conditional knock-out model of APP (APP-KO). In the first part of this work, the role of APP in structural and functional synaptic plasticity is characterised in the cortex and hippocampus. The density and morphology of postsynaptic compartments -the dendritic spines- display reduced plasticity when APP is lacking in both neurons and astrocytes of the cortex. The reduced plasticity does not involve excitatory receptor composition. Selective KO of APP in adjacent astrocytes results in decreased plastic spines in the cortex, while increased spine number and more stable spines are observed in the hippocampus. Additionally, APP-KO mice display functional plasticity deficits in the hippocampus manifested by reduced synaptic signalling strength. The gliotransmitter D-serine is released by astrocytes and potentiates functional plasticity in neurons. As extracellular levels of D-serine are reduced in APP-KO animals, application of D-serine was tested for rescue of the functional plasticity deficits. The second part of this work focuses on the role of APP in astrocytes as active partners in synaptic activity. Spontaneous Ca2+ activity, that is responsible for numerous cellular processes and gliotransmission, was investigated in the astrocytic contact sites to synapses. Ca2+ transients are shown to be reduced in the perisynaptic sites of APP-KO astrocytes in the cortex and hippocampus. The Ca2+ activity is regulated by mitochondria that are dysfunctional in APP-KO astrocytes evidenced by fragmented morphology and prolonged Ca2+ uptake and release duration. In summary, these findings ascribe a physiological role to APP in synaptic plasticity and in associated astrocytic function. These insights are crucial for understanding the biology of AD and for developing new therapeutic strategies.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: amyloid precursor protein, synaptic plasticity, astrocytes, mitochondria, perisynaptic Ca2+
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 540 Chemie
• Fakultäten: Fakultät für Chemie und Pharmazie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 8. Oktober 2018
• 1. Bericht­erstatter:in: Biel, Martin