Increased expression of pathological markers in Parkinson’s disease dementia post-mortem brains compared to dementia with Lewy bodies

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 putamen (CP) regions of human post-mortem brain samples from individuals with PDD and DLB and condition-matched controls. Results We found that p-APPT668 (TC), α-synuclein (CP), and LC3II (CP) are all increased while the tyrosine hydroxylase (TH) (CP) is decreased in both PDD and DLB compared to control. Also, the levels of Aβ42 and DD2R, IBA1, and p-LRRK2S935 are all elevated in PDD compared to control. Interestingly, protein levels of p-TauS199/202 in CP and DD2R, DRP1, and VPS35 in TC are all increased in PDD compared to DLB. Conclusions Together, our comprehensive and systematic study identified a set of signature proteins that will help to understand the pathology and etiology of PDD and DLB at the molecular level.

Evaluation of Memory Impairment Following Prenatal Exposure to Mosquito Coil Smoke

Background: Developmental Neurotoxicity can lead to the buildup of reactive oxygen species which is an indicator to oxidative stress in the prenatally exposed offspring. Neuronal oxidative stress induces neuroinflammation, precedes tangle formation, and disrupts synaptic plasticity. The result of such changes may be expressed into adulthood as behavioral deficits. All together, these mechanisms are implicated in memory disorders. Objectives: To investigate the histochemical changes in the hippocampus and entorhinal cortex of Wistar rats' offspring after prenatal exposure to mosquito coil smoke and its effect on memory. . Methods: 12 pregnant Wistar rats were grouped into four, 3 animals per group. Group I was exposed to fresh air. Groups II, III, and IV were exposed to mosquito coil smoke for 4, 6 and 8 hours daily respectively throughout gestation period. On Post-natal day (PND) 28 and 29, shortterm spatial and recognition memory of adolescent wistar rats were assessed using water licking task and novel object recognition test respectively. For each animal group (I-IV), a total of 8 animals were randomly selected from the litters for neurobehavioral studies. Experimental animals were humanely sacrificed and sections from the hippocampus and entorhinal cortex were processed for histochemical studies using Bielschowsky stain. Data were presented as mean ± SEM; analysed using One-way analysis of variance and Tukey's Multiple Comparison Test (p<0.05). Results and Conclusion: Our results showed significant impairment in short-term recognition and spatial memory of group III and IV adolescent wistar rats when compared with the control (p<0.05) and the formation of neurofibrillary tangle-like structures in neurons of the studied regions. .

Perspectives on the Role of APOE4 as a Therapeutic Target for Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disease that is coupled with chronic cognitive dysfunction. AD cases are mostly late onset, and genetic risk factors like the Apolipoprotein E (APOE) play a key role in this process. APOE ɛ2, APOE ɛ3, and APOE ɛ4 are three key alleles in the human APOE gene. For late onset, APOE ɛ4 has the most potent risk factor while APOE ɛ2 plays a defensive role. Several studies suggests that APOE ɛ4 causes AD via different processes like neurofibrillary tangle formation by amyloid-β accumulation, exacerbated neuroinflammation, cerebrovascular disease, and synaptic loss. But the pathway is still unclear as to what actions of APOE ɛ4 leads to AD development. Since APOE was found to contribute to many AD pathways, targeting APOE ɛ4 can lead to a hopeful plan of action in development of new drugs to target AD. In this review, we focus on recent studies and perspectives, focusing on APOE ɛ4 as a key molecule in therapeutic strategies.

A Comparative Study of Site-Specific Distribution of Aging-Related Tau Astrogliopathy and Its Risk Factors Between Alzheimer Disease and Cognitive Healthy Brains: The Hisayama Study

Knowledge of aging-related tau astrogliopathy (ARTAG) in healthy elderly individuals remains incomplete and studies to date have not focused on the olfactory nerve, which is a vulnerable site of various neurodegenerative disease pathologies. We performed a semiquantitative evaluation of ARTAG in 110 autopsies in the Japanese general population (Hisayama study). Our analysis focused on Alzheimer disease (AD) and cognitive healthy cases (HC), including primary age-related tauopathy. Among the various diseased and nondiseased brains, ARTAG was frequently observed in the amygdala. The ARTAG of HC was exclusively limited to the amygdala whereas gray matter ARTAG in AD cases was prominent in the putamen and middle frontal gyrus following the amygdala. ARTAG of the olfactory nerve mainly consists of subpial pathology that was milder in the amygdala. A logistic regression analysis revealed that age at death and neurofibrillary tangle Braak stage significantly affected the ARTAG of HC. In AD, age at death and male gender had significant effects on ARTAG. In addition, the Thal phase significantly affected the presence of white matter ARTAG. In conclusion, our research revealed differences in the distribution of ARTAG and affected variables across AD and HC individuals.

Molecular Insight Into the Therapeutic Potential of Long Non-coding RNA-Associated Competing Endogenous RNA Axes in Alzheimer’s Disease: A Systematic Scoping Review

Alzheimer’s disease (AD) is a heterogeneous degenerative brain disorder with a rising prevalence worldwide. The two hallmarks that characterize the AD pathophysiology are amyloid plaques, generated via aggregated amyloid β, and neurofibrillary tangle, generated via accumulated phosphorylated tau. At the post-transcriptional and transcriptional levels, the regulatory functions of non-coding RNAs, in particular long non-coding RNAs (lncRNAs), have been ascertained in gene expressions. It is noteworthy that a number of lncRNAs feature a prevalent role in their potential of regulating gene expression through modulation of microRNAs via a process called the mechanism of competing endogenous RNA (ceRNA). Given the multifactorial nature of ceRNA interaction networks, they might be advantageous in complex disorders (e.g., AD) investigations at the therapeutic targets level. We carried out scoping review in this research to analyze validated loops of ceRNA in AD and focus on ceRNA axes associated with lncRNA. This scoping review was performed according to a six-stage methodology structure and PRISMA guideline. A systematic search of seven databases was conducted to find eligible articles prior to July 2021. Two reviewers independently performed publications screening and data extraction, and quantitative and qualitative analyses were conducted. Fourteen articles were identified that fulfill the inclusion criteria. Studies with different designs reported nine lncRNAs that were experimentally validated to act as ceRNA in AD in human-related studies, including BACE1-AS, SNHG1, RPPH1, NEAT1, LINC00094, SOX21-AS1, LINC00507, MAGI2-AS3, and LINC01311. The BACE1-AS/BACE1 was the most frequent ceRNA pair. Among miRNAs, miR-107 played a key role by regulating three different loops. Understanding the various aspects of this regulatory mechanism can help elucidate the unknown etiology of AD and provide new molecular targets for use in therapeutic and clinical applications.

Association of Neurofibrillary Tangle Distribution With Age at Onset–Related Clinical Heterogeneity in Alzheimer Disease: An Autopsy Study

Background and Objective:Patients with earlier age at onset of sporadic Alzheimer’s Disease (AD) are more likely than those with later onset to present with atypical clinical and cognitive features. We sought to determine if this age-related clinical and cognitive heterogeneity is mediated by different topographical distributions of tau-aggregate neurofibrillary tangles (NFTs) or by variable amounts of concomitant non-AD neuropathology.Methods:The relative distribution of NFT density in hippocampus and midfrontal neocortex was calculated, and α-synuclein, TDP-43, and microvascular co-pathologies were staged, in patients with severe AD and age at onset of 51-60 (n=40), 61-70 (n=41), and >70 (n=40) years. Regression, mediation, and mixed effects models examined relationships of pathological findings with clinical features and longitudinal cognitive decline.Results:Patients with later age at onset of AD were less likely to present with non-memory complaints (OR=0.46 per decade, 95%CI: 0.22 – 0.88), psychiatric symptoms (β=-0.66, 95%CI: -1.15 – -0.17), and functional impairment (β=-1.25, 95%CI: -2.34 – -0.16). TDP-43 (OR = 2.00, 95%CI: 1.23 - 3.35) and microvascular co-pathology (OR = 2.02, 95%CI: 1.24 – 3.40) were more common in later onset AD, and α-synuclein co-pathology was not related to age at onset. NFT density in Midfrontal cortex (β = -0.51, 95% CI: -0.72 – -0.31) and Midfrontal/Hippocampal NFT ratio (β = -0.18, 95% CI: -0.26 – -0.10) were lower in those with later age at onset. Executive function (β = 0.48, 95% CI: 0.09 – 0.90) and visuospatial (β = 0.97, 95% CI: 0.46 – 1.46) cognitive deficits were less impaired in patients with later age at onset. Mediation analyses showed that the effect of age at onset on severity of executive function deficits was mediated by Midfrontal/Hippocampal NFT ratio (β = 0.21, 95% CI: 0.08 – 0.38) and not by concomitant non-AD pathologies. Midfrontal/Hippocampal NFT ratio also mediated an association between earlier age at onset and faster decline on tests of global cognition, executive function, and visuospatial abilities.Discussion:Worse executive dysfunction and faster cognitive decline in people with sporadic AD with earlier rather than later age at onset is mediated by greater relative Midfrontal neocortical to hippocampal NFT burden and not by concomitant non-AD neuropathology.

Late Onset Alzheimer Dementia in Patient with Genotype E3/E4: A Case Report

ackground: Alzheimer's dementia (AD) is a neurodegenerative disorder and there is progressive cognitive impairment, functional deficits and behavioral changes. This neurodegenerative disease process is classically characterized by two pathological features: amyloid- β plaque deposition and neurofibrillary tangle of tau hyperphosphorylation. The most established genetic risk factor for late-onset Alzheimer Disease is the APOE gene allele 4. We will report a case of late-onset Alzheimer's Dementia with genotype E3/E4. Case: A 70-years-old woman patient, complained by her family that she often forgets. The Mini Mental State Examination showed disturbances in orientation, attention, calculation and recall. Non-contrast Brain Magnetic resonance imaging examination revealed decrease in hippocampal volume. Patient also performed a molecular examination of the Apolipoprotein E (APOE) genotype and the genotype E3/E4 was detected Conclusion: The APOE E4 gene has a major role in the occurrence of Late-Onset Alzheimer's Dementia. Keywords: Alzheimer Dementia, Apolipoprotein E.

The apolipoprotein receptor LRP3 compromises APP levels

Background Members of the low-density lipoprotein (LDL) receptor family are involved in endocytosis and in transducing signals, but also in amyloid precursor protein (APP) processing and β-amyloid secretion. ApoER2/LRP8 is a member of this family with key roles in synaptic plasticity in the adult brain. ApoER2 is cleaved after the binding of its ligand, the reelin protein, generating an intracellular domain (ApoER2-ICD) that modulates reelin gene transcription itself. We have analyzed whether ApoER2-ICD is able to regulate the expression of other LDL receptors, and we focused on LRP3, the most unknown member of this family. We analyzed LRP3 expression in middle-aged individuals (MA) and in cases with Alzheimer’s disease (AD)-related pathology, and the relation of LRP3 with APP. Methods The effects of full-length ApoER2 and ApoER2-ICD overexpression on protein levels, in the presence of recombinant reelin or Aβ42 peptide, were evaluated by microarray, qRT-PCRs, and western blots in SH-SY5Y cells. LRP3 expression was analyzed in human frontal cortex extracts from MA subjects (mean age 51.8±4.8 years) and AD-related pathology subjects [Braak neurofibrillary tangle stages I–II, 68.4±8.8 years; III–IV, 80.4 ± 8.8 years; V–VI, 76.5±9.7 years] by qRT-PCRs and western blot; LRP3 interaction with other proteins was assessed by immunoprecipitation. In CHO cells overexpressing LRP3, protein levels of full-length APP and fragments were evaluated by western blots. Chloroquine was employed to block the lysosomal/autophagy function. Results We have identified that ApoER2 overexpression increases LRP3 expression, also after reelin stimulation of ApoER2 signaling. The same occurred following ApoER2-ICD overexpression. In extracts from subjects with AD-related pathology, the levels of LRP3 mRNA and protein were lower than those in MA subjects. Interestingly, LRP3 transfection in CHO-PS70 cells induced a decrease of full-length APP levels and APP-CTF, particularly in the membrane fraction. In cell supernatants, levels of APP fragments from the amyloidogenic (sAPPα) or non-amyloidogenic (sAPPβ) pathways, as well as Aβ peptides, were drastically reduced with respect to mock-transfected cells. The inhibitor of lysosomal/autophagy function, chloroquine, significantly increased full-length APP, APP-CTF, and sAPPα levels. Conclusions ApoER2/reelin signaling regulates LRP3 expression, whose levels are affected in AD; LRP3 is involved in the regulation of APP levels.

Ex vivo MRI atlas of the human medial temporal lobe: characterizing neurodegeneration due to tau pathology

Tau neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s disease (AD). To elucidate patterns of structural change in the MTL specifically associated with tau pathology, we compared high-resolution ex vivo MRI scans of human postmortem MTL specimens with histology-based pathological assessments of the MTL. MTL specimens were obtained from twenty-nine brain donors, including patients with AD, other dementias, and individuals with no known history of neurological disease. Ex vivo MRI scans were combined using a customized groupwise diffeomorphic registration approach to construct a 3D probabilistic atlas that captures the anatomical variability of the MTL. Using serial histology imaging in eleven specimens, we labelled the MTL subregions in the atlas based on cytoarchitecture. Leveraging the atlas and neuropathological ratings of tau and TAR DNA-binding protein 43 (TDP-43) pathology severity, morphometric analysis was performed to correlate regional MTL thickness with the severity of tau pathology, after correcting for age and TDP-43 pathology. We found significant correlations between tau pathology and thickness in the entorhinal cortex (ERC) and stratum radiatum lacunosum moleculare (SRLM). When focusing on cases with low levels of TDP-43 pathology, we found strong associations between tau pathology and thickness in the ERC, SRLM and the subiculum/cornu ammonis 1 (CA1) subfields of the hippocampus, consistent with early Braak stages.