Dementia with Lewy Bodies: Molecular Pathology in the Frontal Cortex in Typical and Rapidly Progressive Forms

Abstract

ObjectivesThe 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.MethodsReal-time quantitative PCR, mitochondrial enzymatic assays, and analysis of β-amyloid, tau, and synuclein species were used.ResultsThe 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 involved in energy metabolism and increased expression of enzymes involved in purine metabolism; (iii) abnormal expression of nucleolar proteins, rRNA18S, genes encoding ribosomal proteins, and initiation factors of the transcription at the ribosome; (iv) discrete inflammation; and (v) marked deregulation of brain ORs and TASRs, respectively. Severe mitochondrial dysfunction involving activity of four complexes, minimal inflammatory responses, and dramatic altered expression of ORs and TASRs discriminate DLB from Alzheimer’s disease. Altered solubility and aggregation of α-synuclein, increased β-amyloid bound to membranes, and absence of soluble tau oligomers are common in DLB and rpDLB. Low levels of soluble β-amyloid are found in DLB. However, increased soluble β-amyloid 1–40 and β-amyloid 1–42, and increased TNFα mRNA and protein expression, distinguish rpDLB.ConclusionMolecular alterations in frontal cortex in DLB involve key biochemical pathways such as mitochondria and energy metabolism, protein synthesis, purine metabolism, among others and are accompanied by discrete innate inflammatory response.

Transcriptional network analysis in frontal cortex in Lewy body diseases with focus on dementia with Lewy bodies

“…TASRs are significantly upregulated in frontal cortex in PD and DLB , and our findings further indicate that deregulation of TASRs in frontal cortex occurs in iLBD as well. Previous studies have shown altered protein synthesis machinery in the frontal cortex in PD and DLB from the nucleolus to the ribosome . Nuclear alterations include increased nucleolar stress and altered synthesis of ribosomal RNAs, in addition to altered production of mRNAs.…”

“…Another deregulated cluster in LBD is related to innate inflammatory responses. This has been the subject of two detailed studies in PD and DLB (34,38). An interesting aspect was the downregulation of cytokines and several mediators of the inflammatory response in the substantia nigra at early stages of PD (34) and the relatively low inflammatory response in the frontal cortex in DLB (38), which is in line with previous observations pointing out the relatively low inflammatory response and enhanced dystrophic microglia in DLB (2,88,90).…”

“…It is possible that these receptors in brain are not involved in the perception of odors and taste but rather correspond to new central chemoreceptors looking for putative ligands or interacting complementary receptors . TASRs are significantly upregulated in frontal cortex in PD and DLB , and our findings further indicate that deregulation of TASRs in frontal cortex occurs in iLBD as well. Previous studies have shown altered protein synthesis machinery in the frontal cortex in PD and DLB from the nucleolus to the ribosome .…”

“…This has been the subject of two detailed studies in PD and DLB (34,38). An interesting aspect was the downregulation of cytokines and several mediators of the inflammatory response in the substantia nigra at early stages of PD (34) and the relatively low inflammatory response in the frontal cortex in DLB (38), which is in line with previous observations pointing out the relatively low inflammatory response and enhanced dystrophic microglia in DLB (2,88,90). This is further supported in the present study by downregulation of AIF1, which encodes the microglial marker IBA-1 in the frontal cortex in iLBD, thus suggesting early microglial alteration in LBDs.…”

Diversity of astroglial responses across human neurodegenerative disorders and brain aging

“…Inflammatory responses are disease‐, region‐ and stage‐dependent, thus largely differing in AD, tauopathies, CJD, PD, DLB and ALS . Several cytokines and mediators are expressed in reactive astrocytes in these diseases, although the precise localization of individual inflammatory mediators is largely unknown.…”