Degeneration of β-amyloid-associated cholinergic structures in transgenic APPSW mice

Lüth, Hans-Joachim; Apelt, Jenny; Ihunwo, Amadi O.; Arendt, Thomas; Schliebs, Reinhard

doi:10.1016/s0006-8993(03)02658-1

Cited by 63 publications

(43 citation statements)

References 33 publications

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“…It is interesting to note that these structural alterations in the striatum were not observed in 1.5-month-old APPswe/PS1⌬E9 tg mice, coinciding with the lack of A␤ deposition in the striatum (present study). The fine structure of the dystrophic neurites in the striatum of APPswe/PS1⌬E9 tg mice was similar to those described in the cerebral cortex and hippocampus of APP-overexpressed mice (Masliah et al, 1996;Phinney et al, 1999;Luth et al, 2003) and AD (Masliah et al, 1996). Dystrophic neurites in the striatum, similar to that seen in the hippocampus and cortex of other APP-overexpressing tg mice are located mostly in close proximity to A␤ plaques and contain multilaminar, multivesicular, and dense-core bodies, as well as mitochondria (present study and Phinney et al, 1999;Masliah et al, 1996;Luth et al, 2003).…”

Section: Discussionsupporting

confidence: 83%

“…The fine structure of the dystrophic neurites in the striatum of APPswe/PS1⌬E9 tg mice was similar to those described in the cerebral cortex and hippocampus of APP-overexpressed mice (Masliah et al, 1996;Phinney et al, 1999;Luth et al, 2003) and AD (Masliah et al, 1996). Dystrophic neurites in the striatum, similar to that seen in the hippocampus and cortex of other APP-overexpressing tg mice are located mostly in close proximity to A␤ plaques and contain multilaminar, multivesicular, and dense-core bodies, as well as mitochondria (present study and Phinney et al, 1999;Masliah et al, 1996;Luth et al, 2003). Vesicular organelles have been ultrastructurally identified as part of a lysosomal system in APP-overexpressing tg mice and AD, which have been implicated in different endocytic pathways that are altered in this disease (Cataldo et al, 2000(Cataldo et al, , 2004Mathews et al, 2002).…”

Section: Discussionsupporting

confidence: 75%

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Nigrostriatal Dysfunction in Familial Alzheimer's Disease-Linked APPswe/PS1ΔE9 Transgenic Mice

et al. 2005

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Alzheimer's disease (AD) is often accompanied by extrapyramidal signs attributed to nigrostriatal dysfunction. The association between amyloid deposition and nigrostriatal degeneration is essentially unknown. We showed previously that the striatum and the substantia nigra of transgenic mice harboring familial AD (FAD)-linked APPswe/PS1⌬E9 mutants exhibit morphological alterations accompanied by amyloid-␤ (A␤) deposition (Perez et al., 2004). In the present study, we further investigated the interaction between A␤ deposition and dopaminergic nigrostriatal dysfunction, by correlating morphological and biochemical changes in the nigrostriatal pathway with amyloid deposition pathology in the brains of 3-to 17-month-old APPswe/PS1⌬E9 transgenic mice and age-matched wild-type controls. We show that A␤ deposition is pronounced in the striatum of APPswe/PS1⌬E9 mice at 6 months of age, and the extent of deposition increases in an age-dependent manner. Tyrosine hydroxylase (TH)-positive dystrophic neurites with rosette or grape-like cluster disposition are observed adjacent to A␤ plaques and display multilaminar, multivesicular, and dense-core bodies as well as mitochondria. In addition, an age-dependent increase of TH protein levels are shown in nigral cells in these mutant mice. Using HPLC analysis, we found a reduction in the dopamine metabolite DOPAC in the striatum of these mice. These findings show a close association between amyloid deposition and nigrostriatal pathology and suggest that altered FAD-linked amyloid metabolism impairs, at least in part, the function of dopaminergic neurons.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 75%

Nigrostriatal Dysfunction in Familial Alzheimer's Disease-Linked APPswe/PS1ΔE9 Transgenic Mice

et al. 2005

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“…These findings suggest that the low levels of adenosine in 192IgG-SAP-lesioned animals could only partially inhibit noncholinergic BF neurons that promote wake and EEG activation, thereby failing to fully initiate BF mechanisms that promote recovery sleep and delta. This interpretation is consistent with the report of a blunted increase in recovery NREM delta (Wisor et al, 2005) in a transgenic mouse model of Alzheimer's disease showing loss of cholinergic BF neurons (Masliah et al, 2001) and cortical cholinergic synapses (Luth et al, 2003).…”

supporting

confidence: 92%

Effects of Ibotenate and 192IgG-Saporin Lesions of the Nucleus Basalis Magnocellularis/Substantia Innominata on Spontaneous Sleep and Wake States and on Recovery Sleep after Sleep Deprivation in Rats

Kaur¹,

Junek²,

Black³

et al. 2008

J. Neurosci.

115

110

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The basal forebrain (BF) is known for its role in cortical and behavioral activation, and has been postulated to have a role in compensatory mechanisms after sleep loss. However, specific neuronal phenotypes responsible for these roles are unclear. We investigated the effects of ibotenate (IBO) and 192IgG-saporin (SAP) lesions of the caudal BF on spontaneous sleep-waking and electroencephalogram (EEG), and recovery sleep and EEG after 6 h of sleep deprivation (SD). Relative to artificial CSF (ACSF) controls, IBO injections decreased parvalbumin and cholinergic neurons in the caudal BF by 43 and 21%, respectively, and cortical acetylcholinesterase staining by 41%. SAP injections nonsignificantly decreased parvalbumin neurons by 11%, but significantly decreased cholinergic neurons by 69% and cortical acetylcholinesterase by 84%. IBO lesions had no effect on sleep-wake states but increased baseline delta power in all states [up to 62% increase during non-rapid eye movement (NREM) sleep]. SAP lesions transiently increased NREM sleep by 13%, predominantly during the dark phase, with no effect on EEG. During the first 12 h after SD, animals with IBO and SAP lesions showed lesser rebound NREM sleep (32 and 77% less, respectively) and delta power (78 and 53% less) relative to ACSF controls. These results suggest that noncholinergic BF neurons promote cortical activation by inhibiting delta waves, whereas cholinergic BF neurons play a nonexclusive role in promoting wake. Intriguingly, these results also suggest that both types of BF neurons play important roles, probably through different mechanisms, in increased NREM sleep and EEG delta power after sleep loss.

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“…In particular, hippocampal or cortical neuronal loss and degeneration agree with those observed in dementia models such as ischemia 5) and APP transgenic animals. 36) Selective cell death is common in many agingrelated neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and progressive supranuclear palsy. 37) The neurological disorder that is most clearly associated with TD in humans is Wernicke-Korsakoff syndrome, which is characterized by severe memory loss, cholinergic deficits and selective cell death in specific brain regions.…”

Section: Discussionmentioning

confidence: 99%

Effects of Yokukansan, a Traditional Japanese Medicine, on Memory Disturbance and Behavioral and Psychological Symptoms of Dementia in Thiamine-Deficient Rats

Ikarashi

Iizuka

Imamura

et al. 2009

Biological & Pharmaceutical Bulletin

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Behavioral and psychological symptoms of dementia (BPSD), including anxiety, depression, excitement, anger, hallucination, and roaming, are seen in patients with Alzheimer's disease and other forms of senile dementia. 1,2) To date, although atypical or conventional antipsychotic medications are used to treat BPSD, drug-induced extrapyramidal symptoms and other adverse events are seen. In addition, the Food and Drug Administration warned in 2005 that the antipsychotic medications increase mortality among elderly patients. Therefore, new remedies without adverse effects have been sought.Yokukansan (TJ-54) is a traditional herbal medicine called a 'kampo medicine' in Japan. The Ministry of Health, Labor and Welfare in Japan has approved it as a remedy for neurosis, insomnia, and irritability in children. Recently, TJ-54 has been reported to ameliorate excitement, anger, and hallucination in BPSD in patients with Alzheimer's disease, dementia with Lewy bodies, and other forms of senile dementia. 1,2) However, there is limited research on this compound and the mechanism by which it alters the symptoms of dementia is unknown.Up to now, various dementia models including b-amyloid protein precursor (APP) 3) or a-synuclein transgenic mice, 4) and ischemia 5) or scopolamine 6) -treated animals have been used for research in the pathogenesis and therapy of dementia. However, because most studies focused on deficits of the functions of learning and memory that are the main symptoms of dementia, or because only the abnormalities of learning and memory functions are observed in the most models, information regarding BPSD was few in the animal models. Thus, animal models covering peripheral symptoms like BPSD observed in patients with dementia have little been reported. However, recently, it has been reported that not only impairment of learning and memory but also BPSD-like behaviors such as anxiety, depression, muricide, attacking, and startle responses are observed in thiamine-deficient (TD) rats and mice, 7) i.e., the data about BPSD-like behaviors are more abundant than other dementia models. TD is a critical factor in the etiology of Wernicke-Korsakoff's syndrome, which is characterized by a decrease in thiamine pyrophosphate (biologically active form of thiamine)-dependent enzymes involved in cellular glucose and energy metabolism in the brain.8) Thus, although the pathogenesis (or an induction factor) in each dementia model including TD animals is different, there is a common point that memory dysfunction is observed in each model. Furthermore, similar deficiencies in thiamine pyrophosphate-dependent enzyme activities are reported in postmortem brain tissues of patients with Alzheimer's disease. 9) TD has been also reported to induce selective neuronal loss, 10) cholinergic deficits, 11) and accumulations of the abnormal tau isoforms 12) and APP 13) that are involved in Alzheimer's disease. These findings suggest that TD animals may be a valuable tool for evaluation of pharmacotherapy for BPSD as well as dysfunction ...

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Degeneration of β-amyloid-associated cholinergic structures in transgenic APPSW mice

Cited by 63 publications

References 33 publications

Nigrostriatal Dysfunction in Familial Alzheimer's Disease-Linked APPswe/PS1ΔE9 Transgenic Mice

Nigrostriatal Dysfunction in Familial Alzheimer's Disease-Linked APPswe/PS1ΔE9 Transgenic Mice

Effects of Ibotenate and 192IgG-Saporin Lesions of the Nucleus Basalis Magnocellularis/Substantia Innominata on Spontaneous Sleep and Wake States and on Recovery Sleep after Sleep Deprivation in Rats

Effects of Yokukansan, a Traditional Japanese Medicine, on Memory Disturbance and Behavioral and Psychological Symptoms of Dementia in Thiamine-Deficient Rats

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