Udo Rueb

Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transport

Non-neuronal cells may be pivotal in neurodegenerative disease, but the mechanistic basis of this effect remains ill-defined. In the polyglutamine disease spinocerebellar ataxia type 7 (SCA7), Purkinje cells undergo non-cell-autonomous degeneration in transgenic mice. We considered the possibility that glial dysfunction leads to Purkinje cell degeneration, and generated mice that express ataxin-7 in Bergmann glia of the cerebellum with the Gfa2 promoter. Bergmann glia–specific expression of mutant ataxin-7 was sufficient to produce ataxia and neurodegeneration. Expression of the Bergmann glia–specific glutamate transporter GLAST was reduced in Gfa2-SCA7 mice and was associated with impaired glutamate transport in cultured Bergmann glia, cerebellar slices and cerebellar synaptosomes. Ultrastructural analysis of Purkinje cells revealed findings of dark cell degeneration consistent with excitotoxic injury. Our studies indicate that impairment of glutamate transport secondary to glial dysfunction contributes to SCA7 neurodegeneration, and suggest a similar role for glial dysfunction in other polyglutamine diseases and SCAs.

Brainstem pathology and non-motor symptoms in PD.

Parkinsons disease (PD) is considered a multisystem disorder involving dopaminergic, noradrenergic, serotoninergic, and cholinergic systems, characterized by motor and non-motor symptoms. The causes of the non-motor symptoms in PD are multifactorial and unlikely to be explained by single lesions. However, several evidence link them to damage of specific brainstem nuclei. Numerous brainstem nuclei are engaged in fundamental homeostatic mechanisms, including gastrointestinal regulation, pain perception, mood control, and sleep-wake cycles. In addition, these nuclei are locally interconnected in a complex manner and are subject to supraspinal control. The objective of this review is to provide a better overview of the current knowledge about the consequences of the involvement of specific brainstem nuclei to the most prevalent non-motor symptoms occurring in PD. The multidisciplinary efforts of research directed to these non-nigral brainstem nuclei, in addition to the topographical and chronological spread of the disease - especially in the prodromal stages of PD, are discussed.

Gene expression of neuregulin-1 isoforms in different brain regions of elderly schizophrenia patients

One important risk gene in schizophrenia is neuregulin-1 (NRG1), which is expressed in different isoforms in the brain. To determine if alterations of NRG1 are present in schizophrenia, we measured gene expression of NRG1 and its main isoforms as well as the impact of genetic variation of NRG1 in an exploratory study examining three brain regions instead of only one as published so far. In all, we examined post-mortem samples from 11 schizophrenia patients and eight normal subjects. We investigated gene expression of total NRG1 and isoforms I, II and III by real-time PCR in the prefrontal cortex (Brodmann areas 9 and 10) and right hippocampal tissue. For the genetic study, we genotyped the NRG1 polymorphism SNP8NRG221533, which is within the core haplotype of the original publication. Compared to controls, gene expression of the NRG1 isoform I was decreased and isoform II increased in the prefrontal cortex (BA10) of schizophrenia patients. There were no statistically significant differences between individuals carrying at least one C allele of SNP8NRG221533 compared to individuals homozygous for the T allele. The decreased expression of NRG1 isoform I and overexpression of isoform II may be related to deficits in receptor function as well as abnormal migration and myelination. However, our study sample was small and results of this exploratory study should be verified in a larger sample.

Brainstem: Neglected Locus in Neurodegenerative Diseases

The most frequent neurodegenerative diseases (NDs) are Alzheimer’s disease (AD), Parkinson’s disease (PD), and frontotemporal lobar degeneration associated with protein TDP-43 (FTLD–TDP). Neuropathologically, NDs are characterized by abnormal intracellular and extra-cellular protein deposits and by disease-specific neuronal death. Practically all terminal stages of NDs are clinically associated with dementia. Therefore, major attention was directed to protein deposits and neuron loss in supratentorial (telencephalic) brain regions in the course of NDs. This was also true for PD, although the pathological hallmark of PD is degeneration of pigmented neurons of the brainstem’s substantia nigra (SN). However, PD pathophysiology was explained by dopamine depletion in the telencephalic basal ganglia due to insufficiency and degeneration of the projection neurons located in SN. In a similar line of argumentation AD- and FTLD-related clinical deficits were exclusively explained by supratentorial allo- and neo-cortical laminar neuronal necrosis. Recent comprehensive studies in AD and PD early stages found considerable and unexpected involvement of brainstem nuclei, which could have the potential to profoundly change our present concepts on origin, spread, and early clinical diagnosis of these diseases. In contrast with PD and AD, few studies addressed brainstem involvement in the course of the different types of FTLD–TDP. Some of the results, including ours, disclosed a higher and more widespread pathology than anticipated. The present review will focus mainly on the impact of brainstem changes during the course of the most frequent NDs including PD, AD, and FTLD–TDP, with special emphasis on the need for more comprehensive research on FTLDs.

Locus coeruleus volume and cell population changes during Alzheimer's disease progression: A stereological study in human postmortem brains with potential implication for early-stage biomarker discovery.

Alzheimers disease (AD) progression follows a specific spreading pattern, emphasizing the need to characterize those brain areas that degenerate first. The brainstems locus coeruleus (LC) is the first area to develop neurofibrillary changes (neurofibrillary tangles [NFTs]).

Precortical Phase of Alzheimer's Disease (AD)‐Related Tau Cytoskeletal Pathology

Alzheimers disease (AD) represents the most frequent progressive neuropsychiatric disorder worldwide leading to dementia. We systematically investigated the presence and extent of the AD‐related cytoskeletal pathology in serial thick tissue sections through all subcortical brain nuclei that send efferent projections to the transentorhinal and entorhinal regions in three individuals with Braak and Braak AD stage 0 cortical cytoskeletal pathology and fourteen individuals with Braak and Braak AD stage I cortical cytoskeletal pathology by means of immunostainings with the anti‐tau antibody AT8. These investigations revealed consistent AT8 immunoreactive tau cytoskeletal pathology in a subset of these subcortical nuclei in the Braak and Braak AD stage 0 individuals and in all of these subcortical nuclei in the Braak and Braak AD stage I individuals. The widespread affection of the subcortical nuclei in Braak and Braak AD stage I shows that the extent of the early subcortical tau cytoskeletal pathology has been considerably underestimated previously. In addition, our novel findings support the concept that subcortical nuclei become already affected during an early ‘pre‐cortical’ evolutional phase before the first AD‐related cytoskeletal changes occur in the mediobasal temporal lobe (i.e. allocortical transentorhinal and entorhinal regions). The very early involved subcortical brain regions may represent the origin of the AD‐related tau cytoskeletal pathology, from where the neuronal cytoskeletal pathology takes an ascending course toward the secondarily affected allocortex and spreads transneuronally along anatomical pathways in predictable sequences.

The p62 antibody reveals various cytoplasmic protein aggregates in spinocerebellar ataxia Type 6

Neuronal protein aggregates are considered as pathological hallmarks of various human neurodegenerative diseases, including the so-called CAG-repeat disorders, such as spinocerebellar ataxia Type 6 (SCA6). Since the immunocytochemical findings of an initial post-mortem study using a specific antibody against the disease protein of SCA6 (i.e., pathologically altered alpha-1A subunit of the P/Q type voltage-dependent calcium channel, CACNA1A) have not been confirmed so far, the occurrence and central nervous system distribution of neuronal protein aggregates in SCA6 is still a matter of debate. Owing to the fact that the antibody against the pathologically altered CACNA1A is not commercially available, we decided to apply a recently generated p62 antibody on brain tissue from two clinically diagnosed and genetically confirmed SCA6 patients. Application of this p62 antibody revealed numerous cytoplasmic neuronal inclusions in the degenerated cerebellar dentate nucleus and inferior olive of both SCA6 patients studied, whereby a subset of these aggregates were also ubiquitin-immunopositive. In view of the known role of p62 in protein degradation as well as aggresome/sequestosome formation, the p62 aggregate formation observed in the present study suggests that SCA6 not only is associated with an impairment of the calcium channel function and an elongated polyglutamine stretch in CACNA1A, but also with a defective protein handling by the protein quality control system.

Huntington's disease (HD): the neuropathology of a multisystem neurodegenerative disorder of the human brain.

Huntingtons disease (HD) is an autosomal dominantly inherited, and currently untreatable, neuropsychiatric disorder. This progressive and ultimately fatal disease is named after the American physician George Huntington and according to the underlying molecular biological mechanisms is assigned to the human polyglutamine or CAG‐repeat diseases. In the present article we give an overview of the currently known neurodegenerative hallmarks of the brains of HD patients. Subsequent to recent pathoanatomical studies the prevailing reductionistic concept of HD as a human neurodegenerative disease, which is primarily and more or less exclusively confined to the striatum (ie, caudate nucleus and putamen) has been abandoned. Many recent studies have improved our neuropathological knowledge of HD; many of the early groundbreaking findings of neuropathological HD research have been rediscovered and confirmed. The results of this investigation have led to the stepwise revision of the simplified pathoanatomical and pathophysiological HD concept and culminated in the implementation of the current concept of HD as a multisystem degenerative disease of the human brain. The multisystem character of the neuropathology of HD is emphasized by a brain distribution pattern of neurodegeneration (i) which apart from the striatum includes the cerebral neo‐and allocortex, thalamus, pallidum, brainstem and cerebellum, and which (ii) therefore, shares more similarities with polyglutamine spinocerebellar ataxias than previously thought.

Genetic association of argyrophilic grain disease with polymorphisms in alpha-2 macroglobulin and low-density lipoprotein receptor-related protein genes

Argyrophilic grain disease (AGD) is a neurodegenerative disorder of the aged human brain associated with the formation of abnormal tau protein in specific neurones and macroglial cells. Previously, we reported the association between AGD and the ε2 allele of apolipoprotein E (ApoE). Here, the polymorphisms of the alpha‐2 macroglobulin gene (A2M) and those of the low‐density lipoprotein receptor‐related protein gene (LRP) were assessed in 115 AGD cases and compared with 170 controls. The results reveal an association between AGD and the C766T polymorphism of LRP (P=0.001). In addition, the present study shows that the valine to isoleucine (Val1000Ile) polymorphism of A2M is linked with AGD (P=0.03). By comparison, no relationship between AGD and the intronic 5‐bp deletion/insertion polymorphism of A2M is demonstrable (P=0.8). Finally, this report corroborates and extends our earlier finding in that the frequency of the ε2 allele of ApoE is higher in AGD cases than in controls (17.4% vs. 8.5%, P=0.003), whereas the ε4 allele frequency approximates that in control cases (13.9% vs. 13.2%, P=0.93). This association, however, is only apparent in the presence of the LRP CC genotype. In conclusion, the present study shows that AGD is associated with the LRP, A2M and ApoE genes.

Polyglutamine aggregation in Huntington's disease and spinocerebellar ataxia type 3: similar mechanisms in aggregate formation

Polyglutamine (polyQ) diseases are characterized by the expansion of a polymorphic glutamine sequence in disease‐specific proteins and exhibit aggregation of these proteins. This is combated by the cellular protein quality control (PQC) system, consisting of chaperone‐mediated refolding as well as proteasomal and lysosomal degradation pathways. Our recent study in the polyQ disease spinocerebellar ataxia type 3 (SCA3) suggested a distinct pattern of protein aggregation and PQC dysregulation.