| dc.description.abstracteng | Alzheimer’s Disease (AD) is the most common form of dementia in the elderly population and is neuropathologically characterized by hippocampal neurofibrillary degeneration, chronic inflammation as well as widespread parenchymal and vascular amyloid deposits. These features are remarkably similar to those seen in the heritable disorders Familial British (FBD) and Danish Dementias (FDD). Like β‐amyloid (Aβ) in AD, ABri and ADan peptides are the main components of amyloid deposits in FBD and FDD, respectively, and are produced by proteolytic processing of mutant BRI2. These peptides start with an N‐terminal glutamate, which can be post‐translationally converted into a pyroglutamate‐ (pGlu‐) modified form, a mechanism which is also valid for Aβ peptides in AD.Like pGlu‐Aβ, pGlu‐ABri peptides showed an increased aggregation propensity and both pGlu‐modified ABri and ADan exhibited a higher toxicity on human neuroblastoma cells as compared to their non‐modified counterparts.Novel antibodies, detecting the pGlu‐modified forms of ABri and ADan peptides, were generated. Using these antibodies, abundant extracellular amyloid plaques, as well as vascular and parenchymal deposits were detected in human FBD and FDD brain tissue, as well as in a mouse model for FDD. Further immunostainings of human samples revealed that highly aggregated pGlu‐ABri and pGlu‐ADan peptides are mainly present in plaque cores and central vascular deposits, suggesting that these peptides have seeding properties. Furthermore, ADan peptides were detected in pre‐synaptic terminals of the hippocampus from an FDD mouse model, where they might contribute to impaired synaptic transmission.To investigate the direct role of ADan peptides on neuronal integrity, a novel mouse model was generated, expressing ADan1Q‐34, that showed abundant intracellular transgene expression, especially in hippocampal and cortical regions. Animals obtained from different ADan1Q‐34 transgenic lines showed an impaired spatial reference memory and changes in anxiety comparable to AD mouse models.In addition to the pGlu‐modification of Aβ peptides, another possible mechanism for enhanced amyloid aggregation in AD might be Apolipoprotein E (ApoE) proteolysis. The ApoE4 allele represents the most important risk factor for AD and due to its unique biochemical properties, ApoE4 is more susceptible to proteolysis resulting in the release of toxic fragments. So far, there is a mass of reports discussing the influence of ApoE and its fragments on Aβ clearance and deposition, whereas the impact of Aβ on ApoE fragmentation has not been studied.It could be shown that endogenous, murine ApoE becomes proteolytically processed in several dementia mouse models with amyloid pathology in a manner completely reflecting the human pattern. The major portion of murine ApoE fragments was found in synaptosomal fractions of AD mouse models coinciding with intracellular Aβ aggregation, accumulation of autophagic vacuoles, axonopathy and synaptic loss. In vitro experiments using SH‐SY5Y, Ntera2 and Neuro2a cells suggest that human and murine ApoE fragmentation is putatively driven by intracellular Aβ, whereas exogenous Aβ exclusively leads to increased full‐length ApoE expression.Furthermore, crossing 5XFAD with tau transgenic PS19 mice resulted in drastically enhanced tau pathology, astrocytosis, loss of synapto‐dendritic connections and neurons as well as hippocampal atrophy. This indicates that Aβ and Aβ‐induced ApoE fragments trigger tau phosphorylation either in concert or independently from each other in an upstream event, leading to an accelerated progression of AD pathology.In conclusion, the similarities of ABri and ADan peptides to Aβ in AD suggest that the post‐translational pGlu‐modification of amyloid peptides might represent a general pathological mechanism leading to increased aggregation and toxicity in these forms of degenerative dementias. Moreover, it could be demonstrated that in addition to the well‐ known effects of ApoE on Aβ levels, increased amounts of Aβ (and ADan) peptides in turn promote ApoE proteolysis, which might result in a vicious circle leading to neurodegeneration in dementias. | de |