The evolution of Alzheimer's disease‐related cytoskeletal pathology in the human raphe nuclei

Abstract

The cross-sectional analyses currently available show that the Alzheimer's disease (AD)-related cytoskeletal alterations within the human brain affect variously susceptible areas of the cerebral cortex in a uniform sequence with very little interpatient variability. This sequence has been divided for research and comparative purposes into six stages (cortical NFT/NT-stages I-VI). Among the subcortical nuclei affected in AD are those belonging to the raphe system. Efforts were focused on the lesions present in these nuclei to see in which of the six stages the AD-related cytoskeletal anomalies begin and whether a correlation exists between the AD-related pathology developing within the cerebral cortex and the cytoskeletal damage that occurs in the nuclei of the raphe system. To this end, serial sections from the brainstems of 27 post-mortem cases with stages I-VI of cortical cytoskeletal lesions were examined. The cytoskeletal pathology was visualized using the modified silver iodide-Gallyas staining technique and the antibody AT8. The latter is directed specifically against the abnormally phosphorylated cytoskeletal protein tau. The dorsal raphe nucleus manifests the cytoskeletal lesions early on (stages I-II). The central and linear raphe nuclei, by contrast, do so initially in stages III-IV, and the caudal raphe nuclei register the first changes in stages V-VI. In stages V and VI, the dorsal raphe nucleus displays the most severe cytoskeletal pathology within the raphe system, followed by the central and linear raphe nuclei, whereas the cytoskeletal anomalies in the caudal raphe nuclei are slight. The developing damage within the nuclei of the raphe system correlates with the stages I-VI and, furthermore, progresses in the oral raphe nuclei in close connection with the evolution of the pathological process in cortical projection destinations of these nuclei. As the source of the ascending serotonergic system, the involvement of the oral raphe nuclei may be partially responsible for the early manifestation of the non-cognitive and emotional deficiencies possibly traceable to dysfunctions within the ascending serotonergic system.

Brainstem pathology and non-motor symptoms in PD

“…Its major subnucleus (i.e. supratrochlear nucleus) lies in the mesencephalon and is intercalated between the medial longitudinal fascicle and the aqueduct [67].…”

Amyloid Pathology Is Associated with Progressive Monoaminergic Neurodegeneration in a Transgenic Mouse Model of Alzheimer's Disease

“…MAergic neurodegeneration precedes onset of anxiety-related behaviors in APPswe/PS1⌬E9 mice Because MAergic neurons are involved in emotional behaviors (Zweig et al, 1988;Rub et al, 2000;Parvizi et al, 2001;Grudzien et al, 2007), we asked whether MAergic degeneration in APPswe/ PS1⌬E9 mice is associated with any alterations in emotional behaviors. Mice at different ages were monitored for anxietyrelated behavior on an open-field activity test.…”

“…In addition to the degeneration of cortical and hippocampal neurons, AD is associated with the early and progressive degeneration of monoaminergic (MAergic) neurons [serotonergic (5-HT) neurons in the raphe and the noradrenergic (NA) neurons in the locus ceruleus (LC)] (Marcyniuk et al, 1986;Zweig et al, 1988;German et al, 1992;Rub et al, 2000;Parvizi et al, 2001;Lyness et al, 2003;Grudzien et al, 2007). Analysis of MAergic neuropathology in AD cases indicate that neurons that project to cortex (anterior raphe/LC) are pathologically affected, whereas neurons without cortical projections (posterior raphe/LC) are free of pathological changes (Marcyniuk et al, 1986;German et al, 1992;Parvizi et al, 2001).…”

Early detection of Alzheimer's based on intrinsic measurements

“…Additionally, we can also segment difficult cytoskeletal regions like the raphe nuclei. Progressions of dysfunction in the raphe nuclei are well defined and are correlated with different stages of AD [1]. The different degrees in dysfunctionality in the regions can be explained as 'last in first out' [2], which refers to the principle that the structures that mature late are more vulnerable to early degeneration.…”