The deposition of Abeta protein (Abeta) and the development of neurofibrillary changes are important histopathological hallmarks of Alzheimer disease (AD). In this study, the medial temporal lobe serves as a model for the changes in the anatomical distribution pattern of different types of Abeta-deposits occurring in the course of AD, as well as for the relationship between the development of Abeta-deposition and that of neurofibrillary pathology. In the first of 4 phases of beta-amyloidosis, diffuse non-neuritic plaques are deposited in the basal temporal neocortex. The same plaque type appears in the second phase within the external entorhinal layers pre-beta and pre-gamma, and fleecy amyloid deposits occur in the internal entorhinal layers pri-alpha, pri-beta, pri-gamma, and in CA1. In the third phase, Abeta-deposits emerge in the molecular layer of the fascia dentata, and band-like Abeta-deposits occur in the subpial portion of the molecular layer of both the entorhinal region and the temporal neocortex. In addition, confluent lake-like Abeta-deposits appear in the parvopyramidal layer of the presubicular region. The fourth phase is characterized by diffuse and core-only plaques in CA4. Diffuse plaques evolve sporadically in the external entorhinal layer pre-alpha. Parallel to the evolution of beta-amyloidosis as represented by the 4 phases, neuritic plaques gradually make their appearance in the temporal neocortex, entorhinal region, CA1, the molecular layer of the fascia dentata, and CA4. A prerequisite for their development is the presence of Abeta and the presence of neurofibrillary tangles in neurons targeting the regions where neuritic plaques evolve. Each of the different types of Abeta-deposits, including neuritic plaques, plays a specific role in the distinct developmental sequence as represented by the 4 phases so that the medial temporal lobe inexorably becomes involved to an ever greater extent. The step-for-step involvement of connected anatomical subfields highlights the importance of the entorhino-hippocampal pathways for the expansion of beta-amyloidosis. The 4 phases in the evolution of beta-amyloidosis correlate significantly with the stages of the neurofibrillary pathology proposed by Braak and Braak.

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.

Despite the fact that considerable progress has been made in the last 20 years regarding the three-phase process of ingestion and the lower brain stem nuclei involved in it, no comprehensive descriptions of the ingestion-related lower brain stem nuclei are available for neuropathologists confronted with ingestive malfunctions. Here, we propose guidelines for the pathoanatomical investigation of these nuclei based on current knowledge with respect to ingestion and the nuclei responsible for this process. The application of these guidelines is described by drawing upon the example of the lower brain stem of a male patient with spinocerebellar ataxia type 3, also known as Machado-Joseph disease, who displayed malfunctions during the preparatory phase of ingestion, as well as lingual and pharyngeal phases of swallowing. By way of the representative application of the recommended investigation procedure to 100 microm serial sections through the patient's brain stem stained for lipofuscin pigment and Nissl material, we observed neuronal loss together with astrogliosis in nearly all of the ingestion-related lower brain stem nuclei (motor, principal and spinal trigeminal nuclei; facial nucleus; parvocellular reticular nucleus; ambiguous nucleus, motor nucleus of the dorsal glossopharyngeal and vagal area; gelatinous, medial, parvocellular and pigmented solitary nuclei; hypoglossal nucleus). In view of their known functional role in the three-phase process of ingestion, damage to these nuclei not only offers an explanation of the patient's malfunctions related to the preparatory phase of ingestion and lingual and pharyngeal phases of swallowing, but also suggests that the patient may have suffered from additional esophageal phase swallowing malfunctions not mentioned in his medical records.

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Unstable expansions in the Q22-polyglutamine domain of human ATXN2 mediate risks for motor neuron diseases such as ALS/FTLD or cause the autosomal dominant Spinocerebellar Ataxia type 2 (SCA2), but the pathogenesis is not understood and models are unavailable.We generated a novel knock-in mouse line with CAG100 expansion in Atxn2, transmitted unstably. The mutant protein accumulated in neuronal cytosolic aggregates, with a characteristic pattern of multi-system-atrophy. Loss-of-function phenotypes included less mutant offspring, initial weight gain and motor hyperactivity. Progressive toxic aggregation effects started around 20 weeks in homozygous animals showing weight loss, reduced muscle strength and gait ataxia. Lifespan was decreased. In the cerebellum, neuronal soma and dendrites were remarkably spared. However, myelin proteins MBP, CNP, PLP1 and transcripts Mal, Mobp, Rtn4 decreased markedly, especially adhesion factors MAG and MOG. In neurons, strong reductions were found for mRNAs of perineuronal elements Hapln1, Hapln2, Hapln4, of axonal myelin interactors Prnp and Klk6. At protein level, the adhesion factor neuroplastin and neurofilaments were strongly reduced, while presynaptic alpha-synuclein increased two-fold.Overall, this authentic SCA2 mouse model elucidates how altered function and aggregation toxicity of ATXN2 conspire to trigger axon-myelin disconnection. This model will promote the development of neuroprotective therapies and disease biomarkers.