Dynamin 1 concentration in the prefrontal cortex is associated with cognitive impairment in Lewy body dementia (original) (raw)
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BMC Neuroscience, 2022
Background Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are common age-related neurodegenerative diseases comprising Lewy body spectrum disorders associated with cortical and subcortical Lewy body pathology. Over 30% of PD patients develop PD dementia (PDD), which describes dementia arising in the context of established idiopathic PD. Furthermore, Lewy bodies frequently accompany the amyloid plaque and neurofibrillary tangle pathology of Alzheimer’s disease (AD), where they are observed in the amygdala of approximately 60% of sporadic and familial AD. While PDD and DLB share similar pathological substrates, they differ in the temporal onset of motor and cognitive symptoms; however, protein markers to distinguish them are still lacking. Methods Here, we systematically studied a series of AD and PD pathogenesis markers, as well as mitochondria, mitophagy, and neuroinflammation-related indicators, in the substantia nigra (SN), temporal cortex (TC), and caudate and putam...
Decrease of dynamin 2 levels in late-onset Alzheimer’s disease alters Aβ metabolism
Biochemical and Biophysical Research Communications, 2009
Alzheimer's disease Dynamin Amyloid-b peptide Amyloid precursor protein Lipid raft a b s t r a c t Late-onset Alzheimer's disease (LOAD) is significantly associated with a single nucleotide polymorphism located in the dynamin (DNM) 2 gene, especially in non-carriers of the apolipoprotein E-e4 allele. In this study we used real-time PCR to show that DNM2 mRNA is significantly reduced in the cortex of AD brains and in the peripheral blood of dementia patients. Neuroblastoma cells transfected with a dominant negative DNM2 had increased amyloid beta protein (Ab) secretion and most of the amyloid precursor protein (APP) in these cells was localized to the plasma membrane. In addition, these cells were rich in flotillin, which is a component of lipid rafts. These data suggest that DNM2 expression is reduced in LOAD, which results in the accumulation of APP in lipid raft-rich plasma membranes. Consequently, Ab secretion may increase in LOAD neurons.
Synaptic protein deficits are associated with dementia irrespective of extreme old age
Neurobiology of Aging, 2012
Recent evidence shows that despite high incidence of dementia in the very old, they exhibit significantly lower levels of Alzheimer's disease (AD) neuropathology relative to younger persons with dementia. The levels and distributions of some synaptic proteins have been found to be associated with dementia severity, even in the oldest-old, but the molecular and functional nature of these deficits have not been studied in detail. The objective of this study was to assess the relationship of dementia with gene and protein expression of a panel of synaptic markers associated with different synaptic functions in young-, middle-, and oldest-old individuals. The protein and messenger RNA (mRNA) levels of 7 synaptic markers (complexin-1, complexin-2, synaptophysin, synaptobrevin, syntaxin, synaptosomal-associated protein 25 (SNAP-25), and septin-5) were compared in the brains of nondemented and demented individuals ranging from 70 to 103 years of age. One hundred eleven brains were selected to have either no significant neuropathology or only AD-associated pathology (neuritic plaques [NPs] and neurofibrillary tangles [NFTs]). The cohort was then stratified into tertiles as young-old (70 -81 years old), middle-old (82-88), and oldest-old (89 -103). The brains of persons with dementia evidenced significantly lower levels of gene and protein expression of synaptic markers regardless of age. Importantly, dementia was associated with reductions in all measured synaptic markers irrespective of their role(s) in synaptic function. Although other dementia-associated hallmarks of AD neuropathology (neuritic plaques and neurofibrillary tangles) become less prominent with increasing age, synaptic marker abnormalities in dementia remain constant with increasing age and may represent an independent substrate of dementia spanning all ages. (M. Schnaider Beeri).
Low-abundant cerebrospinal fluid proteome alterations in dementia with Lewy bodies
Journal of Alzheimer's disease : JAD, 2013
Dementia with Lewy bodies (DLB) is one of the most common neurodegenerative diseases and shares multiple clinical and neuropathological parallels with Alzheimer's (AD) and Parkinson's disease (PD). A variety of clinical signs are suggestive for the diagnosis, and imaging (βCIT SPECT) contributes substantially to the diagnosis. The study reported here was performed in search for a biomarker in the cerebrospinal fluid (CSF) of these patients. We applied 2D fluorescence difference gel electrophoresis and mass spectrometry to analyze the CSF proteome pattern of DLB patients after depleting twelve high-abundant proteins. The densitometric analysis of 2D gels showed the up- or down-regulation of 44 protein spots. Subsequently, 23 different proteins were identified. The majority is involved in acute phase and immune response. Many of these proteins were previously reported before as being associated with AD or PD, which strongly suggests a molecular cross-talk and may explain clini...
Cortical Lewy bodies and Alzheimer-type changes in patients with Parkinson's disease
Acta Neuropathologica, 1998
We investigated the role of cortical Lewy bodies (LB) and Alzheimer-type changes in cognitive impairment in patients with idiopathic Parkinson's disease (PD). We evaluated 44 cases for the extent of neuropathological lesions with a CERAD neuropathological assessment battery and the stage of dementia using Reisberg's global deterioration scale (GDS). Substantia nigra, amygdala, hippocampus and cerebral cortex were examined for LB and Alzheimer-type changes. For detection of LB, the cortical areas were stained with polyclonal antibodies against ubiquitin and tau. We found at least one cortical LB in 93% of cases. Furthermore, 43% of the cases had histological findings of definite Alzheimer's disease (AD). The association between cognitive impairment and the number of cortical LB and Alzheimer-type changes in the amygdala, hippocampus and six selected gyri from cerebral cortex were analyzed using stepwise linear regression. In this analysis the total number of cortical LB, and the amount of neurofibrillary tangles in the temporal cortex remained statistically significant. When the cases with neuropathological changes consistent with a diagnosis of AD were excluded, the correlation between the total number of cortical LB and cognitive impairment was more obvious. A stepwise linear regression analysis in these cases found the total number of cortical LB to be the statistically significant predictor of cognitive impairment. This study revealed that LB densities in the cortex, especially in the temporal neocortex, correlated significantly with the cognitive impairment in PD independent of or in addition to Alzheimertype pathology.
Frontiers in neurology, 2017
The goal of this study was to assess mitochondrial function, energy, and purine metabolism, protein synthesis machinery from the nucleolus to the ribosome, inflammation, and expression of newly identified ectopic olfactory receptors (ORs) and taste receptors (TASRs) in the frontal cortex of typical cases of dementia with Lewy bodies (DLB) and cases with rapid clinical course (rpDLB: 2 years or less) compared with middle-aged non-affected individuals, in order to learn about the biochemical abnormalities underlying Lewy body pathology. Real-time quantitative PCR, mitochondrial enzymatic assays, and analysis of β-amyloid, tau, and synuclein species were used. The main alterations in DLB and rpDLB, which are more marked in the rapidly progressive forms, include (i) deregulated expression of several mRNAs and proteins of mitochondrial subunits, and reduced activity of complexes I, II, III, and IV of the mitochondrial respiratory chain; (ii) reduced expression of selected molecules invol...
Journal of Neurochemistry, 2019
Lewy body diseases share clinical, pathological, genetic and biochemical signatures, and are regarded as a highly heterogeneous group of neurodegenerative disorders. Inclusive of Parkinson's disease (PD), Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), controversy still exists as to whether they should be considered as separate disease entities or as part of the same disease continuum. Here we discuss emerging knowledge relating to both clinical, and neuropathological differences and consider current biomarker strategies as we try to improve our diagnostic capabilities and design of disease modifying therapeutics for this group of debilitating neurodegenerative disorders. image This article is part of the Special Issue “Synuclein”.
Alzheimer's Research & Therapy, 2014
Introduction: Lewy body and Alzheimer-type pathologies often co-exist. Several studies suggest a synergistic relationship between amyloid-β (Aβ) and α-synuclein (α-syn) accumulation. We have explored the relationship between Aβ accumulation and the phosphorylation of α-syn at serine-129 (pSer129 α-syn), in post-mortem human brain tissue and in SH-SY5Y neuroblastoma cells transfected to overexpress human α-syn. Methods: We measured levels of Aβ40, Aβ42, α-syn and pSer129 α-syn by sandwich enzyme-linked immunosorbent assay, in soluble and insoluble fractions of midfrontal, cingulate and parahippocampal cortex and thalamus, from cases of Parkinson's disease (PD) with (PDD; n = 12) and without dementia (PDND; n = 23), dementia with Lewy bodies (DLB; n = 10) and age-matched controls (n = 17). We also examined the relationship of these measurements to cognitive decline, as measured by time-to-dementia and the mini-mental state examination (MMSE) score in the PD patients, and to Braak tangle stage. Results: In most brain regions, the concentration of insoluble pSer129 α-syn correlated positively, and soluble pSer129 α-syn negatively, with the levels of soluble and insoluble Aβ. Insoluble pSer129 α-syn also correlated positively with Braak stage. In most regions, the levels of insoluble and soluble Aβ and the proportion of insoluble α-syn that was phosphorylated at Ser129 were significantly higher in the PD and DLB groups than the controls, and higher in the PDD and DLB groups than the PDND brains. In PD, the MMSE score correlated negatively with the level of insoluble pSer129 α-syn. Exposure of SH-SY5Y cells to aggregated Aβ42 significantly increased the proportion of α-syn that was phosphorylated at Ser129 (aggregated Aβ40 exposure had a smaller, non-significant effect). Conclusions: Together, these data show that the concentration of pSer129 α-syn in brain tissue homogenates is directly related to the level of Aβ and Braak tangle stage, and predicts cognitive status in Lewy body diseases.