TY  - GEN
A1  - Sotiropoulos, Ioannis
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/7024/
AV  - public
N2  - Clinical evidence suggests the involvement of stress and glucocorticoids (GC) in the etiopathogenesis of Alzheimer?s disease (AD), a disease marked by severe memory impairments as well as alterations in mood and emotional state. The experiments described in this dissertation represent an attempt to establish the cellular mechanisms through which stress and GC may impact on the development of AD. These studies focused on the hippocampus and prefrontal cortex (PFC), brain areas that are severely affected in AD; both areas were found to respond to stress and GC hypersecretion with neuronal atrophy and death, effects that are mediated by glucocorticoid receptors (GR). Furthermore, stress and GC were shown to induce impairments in cognitive behaviors which depend on the structural integrity of the hippocampus and PFC. The neurodegeneration which accompanies AD is characterized by mis-processing of the amyloid precursor protein (APP) and abnormal hyperphosphorylation of the microtubule-associated protein tau; the latter leads to cytoskeletal disruption and synaptic loss. Experiments in laboratory animals and cell systems established that stress/GC can contribute to AD pathology by triggering the amyloidogenic pathway of APP processing by increasing the expression of APP-cleaving enzymes (BACE and nicastrin), giving rise to the APP C-terminal fragment 99 (C99) which, after further processing, yields amyloid beta (A?). While A? is the APP product to which AD pathology is usually ascribed, C99 also has deleterious effects on neuronal survival and cognition. The present studies showed that stress/GC-induced changes in APP processing were paralleled by impairments in hippocampus- and PFC-dependent behaviors and anxiety (in animals), as well as by increased abnormal hyperphosphorylation of tau, decreased tau degradation, and reduced stability of microtubules; additional evidence obtained suggests that synaptic loss may also be a consequence of stress/GC-induced alterations in APP processing and tau biochemistry. A more detailed analysis of the mechanisms through which GC (the main physiological response to stress) might influence tau revealed the involvement of a number of kinases (GSK3?, cdk5 and MAPK), all of which have been implicated in AD pathology. Since normal laboratory species do not develop AD pathology unless they are engineered to express human forms of APP or tau, one part of this work examined whether GC could induce their harmful effects in a rat neuronal cell line that had been stably transfected with htau. The results of those experiments confirmed the hypothesis that htau is responsible for making neurons sensitive to the AD-like pathological effects of GC; specifically, as compared to wild-type cells, those expressing htau showed increased sensitivity to GC and A?, while at the same time increasing APP mis-processing to C99 and A?, as well as tau hyperphosphorylation. In summary, these experiments describe, for the first time, the processes through which stress/GC can lead to AD-like pathology. They raise the hypothesis that stress/GC primarily trigger APP mis-processing, which then leads to tau kinase activation and tau pathology; the tau kinases then feeds back to exacerbate the pathobiochemistry in a positive feedback loop. Lastly, the results reported herein suggest new preventative and therapeutic strategies, and also suggest that the AD-related proteins tau and APP may be general key players in mediating the effects of stress and GC in stress-related disorders.
ID  - heidok7024
N1  - Teile in: Journal of Psychiatric Research 39: 451-460
Y1  - 2006///
TI  - Identification of the cellular mechanisms undelying the contribution of stress and glucocorticoids to Alzheimer's disease pathology
KW  - Alzheimer's 
KW  -  stress 
KW  -  glucocorticoids 
KW  -  APP 
KW  -  amyloid 
KW  -  tau 
KW  -  cognition
ER  -