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The physiological importance of the Alzheimer protein

While the role of the amyloid precursor protein (APP) in the development of amyloid plaques that are characteristic of Alzheimer’s disease is well known, the physiological role of this protein in the brain has remained elusive. However, the molecular biologist Professor Dr. Ulrike Müller from Heidelberg has now shown in mouse models that components of the APP gene family play a major role in synaptic plasticity, learning and memory.

Prof. Dr. Ulrike Müller © private

The insoluble protein deposits known as amyloid plaques that are found in the brains of Alzheimer’s patients result from the accumulation of protein fragments known as beta amyloid (Aβ) peptide (with a length of 39 to 43 amino acids). It is formed after sequential cleavage of the amyloid precursor protein (APP), a large protein in the membrane of neurons. In a reaction cascade known as β processing, APP is first cleaved by a β-secretase, snipping off a large soluble fragment (soluble APPβ) into the extracellular space. The remaining part, which stays in the membrane of the neuron, is subsequently cleaved by the protein complex of the enzyme γ-secretase, also located in the membrane. These cleavage processes give rise to the Aβ peptide which accumulates in the extracellular space and prevents communication between neurons, resulting in the death of the neurons.

This process is considered to be the major cause of Alzheimer’s. The role of APP in the pathogenesis of Alzheimer’s has been subject to intensive research. Its key role is also shown in familial (i.e. genetic) forms of Alzheimer’s that are associated with mutations of the APP gene. The normal physiological role of APP has long remained elusive, although it is a common membrane protein of neurons  (and other cell types) in both threadworms (C. elegans) and human beings. The molecular biologist Professor Dr. Ulrike Müller has now published new findings using mice as model systems that could contribute to solving the puzzle. She is the director of the Department of Functional Genetics at the Institute of Pharmacy and Molecular Biotechnology at Universität Heidelberg. She was awarded the Alzheimer Research Prize for her achievements in 2008 (see also Alzheimer Research Prize for Ulrike Müller).

Amyloidogenic (β) and non-amyloidogenic (α) processing of APP © Alzheimer Forum
In addition to β processing (also known as amyloidogenic processing) there is an alternative, non-amyloidogenic APP mechanism. α (alpha) processing involves the enzyme α-secretase, which cleaves APP within the Aβ domain, resulting in a large soluble fragment (sAPPα) that is secreted into the extracellular space. The subsequent cleavage of the remaining membrane-bound APP fragment does not lead to an Aβ peptide, which could be toxic. In cooperation with scientists from the Neuroscience Center at the University Hospital Frankfurt/Main, Ulrike Müller and her colleagues have shown that APPα protects and stimulates the growth of neurons. Prof. Müller is the spokesperson for the DFG-funded CRC/Transregio project “Physiological functions of the APP gene family in the central nervous system” which involves seven teams of researchers from the Universities of Heidelberg, Frankfurt and Mainz and the Kaiserslautern and Braunschweig Universities of Technology.

Mouse models

The researchers used animal models to determine the physiological role of APP. They generated APP knockout mice using embryonic stem cells in which APP was inactivated by way of homologous recombination. APP deficient mice exhibited retarded growth, suffered epileptic seizures, behavioural deficits and other disorders. However, these are minor deficits in view of the widespread expression and evolutionary conservation of APP, and may reflect functional compensation by homologous proteins of the same gene family.

Chimeric mouse from Prof. Ulrike Müller’s laboratory. © IPMB, Universität Heidelberg

The researchers assumed that the functional compensation was caused by two closely related proteins known as “APP-like proteins” (APLP1 and APLP2). To examine the potential functional redundancies within the APLP family, the researchers extended their investigations to APLP knockout mice and also generated double- or triple-mutant mice lacking either individual or all possible combinations of APP-family members by crossing mice with individual mutants. Mice lacking two or all three proteins of the APP family died shortly after birth. They displayed histopathological abnormalities in the brain and in the transmission of signals as a result of reduced cell-cell contacts and reduced connection with the extracellular nervous tissue matrix. They display histopathological abnormalities in the brain which are the result of reduced levels of cell-cell contact and connection with the extracellular nervous tissue matrix. The mice die because of the impaired transmssion of neuronal stimuli between the motor neurons and muscle cells.

The researchers introduced a stop codon into the APP gene to generate a mouse mutant that expressed the soluble sAPPα instead of the complete APP protein. This enabled them to investigate the role of sAPPα during the animals’ development. The researchers found that sAPPα was sufficient to compensate deficits arising from APP deficiency. In a paper published in 2011 (Weyer et al., 2011), the researchers from Heidelberg described how they combined the sAPPα mutant with an APLP2 mutant mouse. The results not only show that the APP gene family plays a key role in the physiological roles of neurons, they also show a relation between disorders in APP processing and memory loss in Alzheimer’s.

Synaptic plasticity

There is a synergistic relationship in the function of sAPPα and sAPLP2α with regard to the formation and maintenance of the synaptic connections between neurons, the maturation of synaptic structures and the release of transmitter molecules. This has been shown using microscopes to examine synapses that connect motor neurons and muscle cells. The ability of synapses between two neurons to change in strength, which is known as synaptic plasticity, was identified as a key mechanism in learning processes which, when damaged, results in memory loss, which is the specific and tragic hallmark of Alzheimer’s. This is the specific, and tragic, hallmark of Alzheimer’s. Working together with scientists from the Braunschweig University of Technology (Prof. Martin Korte), Ulrike Müller showed that the interaction of sAPPα und sAPLP2α plays a key role in enhancing signal transmission between active synapses during learning, a process that is referred to as long-term potentiation.

Studies have shown that Alzheimer’s dementia is associated with lower concentrations of sAPPα in the cerebrospinal fluid and that the activity of α-secretase (the enzyme that snips sAPPα off from APP) decreases as the disease progresses. Together with the research results obtained by Ulrike Müller, these findings suggest that the search for new Alzheimer’s disease treatments should focus on sAPPα, which is the domain of the APP protein that is secreted into the extracellular space and which plays a key role in synaptic plasticity, learning and memory.

References:

Weyer SW, Klevanski M, Delekatge A, Voikar V, Aydin D, Hick M, Filippov M, Drost N, Schaller KL, Saar M, Vogt MA, Gass P, Samata A, Jäschke A, Korte M, Wolfer DP, Caldwell JH, Müller UC: APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP. EMBO J. 2011 Jun 1;30(11): 2266-80.

Tschäpe J-A, Müller UC: Funktionen jenseits der Plaquebildung. Genomexpress 1.12, May 2012: 19-20.

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