Thomas A. Bayer

Intraneuronal Aβ accumulation precedes plaque formation in β-amyloid precursor protein and presenilin-1 double-transgenic mice

beta-Amyloid peptides are key molecules that are involved in the pathology of Alzheimers disease (AD). The source and place of the neurotoxic action of Abeta, however, is still a matter of controversial debates. In the present report, we studied the neuropathological events in a transgenic mouse model expressing human mutant beta-amyloid precursor protein and human mutant presenilin-1 in neurons. Western blot and immunohistochemical analysis revealed that intracellular Abeta staining preceded plaque deposition, which started in the hippocampal formation. At later stages, many neuritic Abeta positive plaques were found in all cortical, hippocampal and many other brain areas. Interestingly, intraneuronal Abeta staining was no longer detected in the brain of aged double-transgenic mice, which correlates with the typical neuropathology in the brain of chronic AD patients.

Evidence for activation of microglia in patients with psychiatric illnesses

Activation of microglia/macrophages is a key event in response to pathological changes in the CNS. HLA-DR is a valuable immunohistochemical marker that specifically reacts with activated microglia cells. In order to elucidate a potential role of microgliosis in severe psychiatric illnesses, post-mortem frontal cortex and hippocampus of patients with schizophrenia (n = 14) and affective disorder (n = 6) and control specimens (n = 13) were studied. Additionally Alzheimers disease cases (n = 8) were included as a human model system with typical neurodegenerative alterations and microglia activation. All patient groups revealed subjects with abundant microglia immunostaining (schizophrenia, three patients; affective disorder, one patient; Alzheimers disease, four patients) in both gray and white matter. This finding provides evidence for distinct neuropathological changes in brains of patients with schizophrenia and affective disorder. The activation of microglia cells, which represent a major part of the brain immune response, may help to unravel the pathophysiological processes in severe psychiatric illnesses.

Genetic and non-genetic vulnerability factors in schizophrenia: the basis of the "two hit hypothesis".

Schizophrenia is a psychiatric disorder that aCicts 0.5‐1% of the general population. It is clinically characterized by disturbed thought processes, delusions, hallucinations and/or reduced social skills (Andreasen, 1995). This severe mental disorder strikes human beings in their early adulthood, causes lifelong disability for most of the suAerers and is therefore one of the ten most expensive disorders worldwide. Its direct and indirect costs mount up to 33 billion dollars per year, while aCicting all ethic backgrounds, genders, socioeconomic classes and nationalities. The course of the illness is characterized by episodes of acute psychotic symptoms followed by phases of remission where symptoms like reduced drive and aAect as well as disturbed cognitive functions prevail. Despite the severeness of the disorder its origins are unclear until now. The neuropathological and neuroanatomical findings in patients with schizophrenia have been proposed to arise from dysfunction of structural reorganization during early brain development (Waddington, 1993; Weinberger, 1995), or postnatally from altered maturation of synaptic elimination (Feinberg, 1982). Morphometric and in vivo neuroimaging studies described enlarged ventricles, cerebral atrophy of temporal lobe and prefrontal structures, and increase in the gyrification index (Arnold and Trojanowski, 1996). One of the most consistent results is the lack of astrogliosis in schizophrenic brains, which would be a requirement for severe and chronic neurodegenerative

Review of immunological and immunopathological findings in schizophrenia.

The involvement of immunological and immunopathological mechanisms in the etiopathogenesis of schizophrenia has been a matter of research, with recently increasing effort. This article reviews the findings focusing on postmortem neuropathology, the blood-brain barrier, antibodies, acute phase proteins, immunocompetent cells, and activation markers of immunocompetent cells. Evidence for the two primarily postulated hypotheses (the infectious hypothesis and the autoimmune hypothesis) is critically discussed. On the basis of the findings, perspectives for future research are outlined aiming at a precise and consequent strategy to elucidate a potential involvement of immune mechanisms in the etiopathogenesis of schizophrenia.

A genetic variation of the inflammatory cytokine interleukin‐6 delays the initial onset and reduces the risk for sporadic Alzheimer's disease

Local inflammatory processes surrounding the amyloid plaques contribute to the progression and acceleration of the Alzheimers disease (AD)–related neurodegeneration. Interleukin‐6 (IL‐6) is an inflammatory cytokine with possible involvement in the local immune response occurring in the central nervous system of AD patients. We tested the hypothesis as to whether a genetic polymorphism of the IL‐6 gene (IL‐6) modifies the age at onset and risk for sporadic AD. Our results support an association of the C allele of the IL‐6 genotype with a delayed initial onset and reduced disease risk and indicate that genetically determined alterations of the immune response may modify the course of AD. Ann Neurol 1999;45:666–668

Key factors in Alzheimer's disease: β-Amyloid precursor protein processing, metabolism and intraneuronal transport

During the last years it has become evident that the β‐amyloid (Aβ) component of senile plaques may be the key molecule in the pathology of Alzheimers disease (AD). The source and place of the neurotoxic action of Aβ, however, is still a matter of controversy. The precursor of the β‐amyloid peptide is the predominantly neuronal β‐amyloid precursor protein. We, and others, hypothesize that intraneuronal misregulation of APP leads to an accumulation of Aβ peptides in intracellular compartments. This accumulation impairs APP trafficking, which starts a cascade of pathological changes and causes the pyramidal neurons to degenerate. Enhanced Aβ secretion as a function of stressed neurons and remnants of degenerated neurons provide seeds for extracellular Aβ aggregates, which induce secondary degenerative events involving neighboring cells such as neurons, astroglia and macrophages/microglia.

No evidence for astrogliosis in brains of schizophrenic patients. A post-mortem study

Schizophrenia is clinically and neuropsychologically characterized by severe cognitive and functional impairment suggesting the presence of a neurodegenerative process in the brains of affected individuals. A variety of neuroanatomical changes have been described such as loss and disorientation of neurons in grey and white matter and cortical atrophy. However, the neuropathological basis for schizophrenia is still unclear. In the present study we monitored the density of GFAP‐positive astrocytes in brains of 33 schizophrenic patients and 26 healthy controls. Both grey matter (entorhinal cortex and subiculum) and white matter (premotor cortex, subventricular zone of the third ventricle and next to inferior horn) structures were measured bilaterally. The overall finding was that there is no evidence for increased astrogliosis in brains of schizophrenic patients vs healthy controls. Therefore, degeneration is unlikely to be the main neuropathological mechanism in schizophrenic brains.

Intraneuronal APP/Aβ Trafficking and Plaque Formation in β-Amyloid Precursor Protein and Presenilin-1 Transgenic Mice

Neuropil deposition of β‐amyloid peptides Aβ40 and Aβ42 is believed to be the key event in the neurodegenerative processes of Alzheimers disease (AD). Since Aβ seems to carry a transport signal that is required for axonal sorting of its precursor β‐amyloid precursor protein (APP), we studied the intraneuronal staining profile of Aβ peptides in a transgenic mouse model expressing human mutant APP751 (KM670/671NL and V717I) and human mutant presenilin‐1 (PS‐1 M146L) in neurons. Using surface plasmon resonance we analyzed the Aβ antibodies and defined their binding profile to APP, Aβ40 and Aβ42. Immunohistochemical staining revealed that intraneuronal Aβ40 and Aβ42 staining preceded plaque deposition, which started at 3 months of age. Aβ was observed in the somatodendritic and axonal compartments of many neurons. Interestingly, the striatum, which lacks transgenic APP expression harbored many plaques at 10 months of age. This is most likely due to an APP/Aβ transport problem and may be a model region to study APP/Aβ trafficking as an early pathological event.

α-Synuclein accumulates in Lewy bodies in Parkinson's disease and dementia with Lewy bodies but not in Alzheimer's disease β-amyloid plaque cores

A growing body of evidence suggests that the non-Aβ component of Alzheimers disease amyloid precursor protein (NACP) or α-synuclein contributes to the neurodegenerative processes in Alzheimers disease (AD), Parkinsons disease (PD) and dementia with Lewy bodies (DLB). In the present study antisera to the N terminus and the NAC domain of the α-synuclein protein were employed to elucidate the expression pattern in brains of patients with AD, PD, DLB and control specimen. α-Synuclein exhibited an overall punctuate expression profile compatible with a synaptic function. Interestingly, while Lewy bodies were strongly immunoreactive, none of the α-synuclein antisera revealed staining in mature β-amyloid plaques in AD. These observations suggest that α-synuclein does not contribute to late neurodegenerative processes in AD brains.

Low frequency of SV40, JC and BK polyomavirus sequences in human medulloblastomas, meningiomas and ependymomas.

Several reports have suggested a role for polyomaviruses in the pathogenesis of human brain tumors.This potential involvement is not conclusively resolved. For the present study, a highly sensitive PCR‐assay with fluorescence‐labelled primers was developed to search for polyomavirus sequences in human brain tumor and control DNA samples. The assay was shown to detect approximately one viral large T‐antigen (TAg) gene per 250 cells. We identified simian virus 40 (SV40)‐like sequences in 2/116 medulloblastomas, in 1/131 meningiomas, in 1/25 ependymomas and in 1/2 subependymomas. A single case of ependymoma contained SV40 VP‐1 late gene sequences. Moreover, one of the meningioma samples showed JC virus sequences. In contrast, 60 hepatoblastoma samples and 31 brain samples from schizophrenic patients were consistently negative. BK virus sequences were not detectable in any of our samples. Immunohistochemical analysis of two SV40 positive tumor biopsies failed to detect large TAg in the tumor cells. In the JC positive meningioma, immunoreactivity for the viral late gene product (VP‐1) was not observed. Our data do not entirely rule out SV40 and JC virus as an initiative agent with a hit‐and‐run mechanism. However the low frequency of virus sequences and the absence of TAg protein expression argue against a major role of these viruses in the pathogenesis of human medulloblastomas, meningiomas and ependymomas.