Postmortem Alzheimer's Disease Research Articles

Systemic Inflammation Causes Microglial Dysfunction With a Vascular AD phenotype

BackgroundStudies in rodents and humans have indicated that inflammation outside CNS (systemic inflammation) affects brain homeostasis contributing to neurodevelopmental disorders. Itis becoming increasingly evident that such early insults may also belinked to neurodegenerative diseases like late-onset Alzheimer's disease (AD). Importantly, lifestyle and stress, such as viral or bacterial infection causing chronic inflammation, may contribute to neurodegenerative dementia. Systemic inflammatory response triggers a cascade of neuroinflammatory responses, altering brain transcriptome, cell death characteristic of AD, and vascular dementia. Our study aimed to assess the temporal evolution of the pathological impact of systemic inflammation evoked by prenatal and early postnatal peripheral exposure of viral mimetic Polyinosinic:polycytidylic acid (PolyI:C) and compare the hippocampal transcriptomic changes with the profiles of human post-mortem AD and vascular dementia brain specimens. MethodsWe have engineered the PolyI:C sterile infection model in wildtype C57BL6 mice to achieve chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyI:C and Saline control mice (3 months, 6 months, 9 months, and 16 months), taking the hippocampus as a reference brain region, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD, and Controls (CTL), in parallel to Vascular dementia (VaD) patients’ specimens. ResultsWe found that PolyI:C mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyI:C brains, microglia undergo aging-dependent morphological shifts progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression throughout aging, with a peak in differential expression at 9 months. We show that the proinflammatory marker Lcn2 is one of the genes with the strongest upregulation in PolyI:C mice upon aging. Validation in brains from patients with increasing severity of AD and VaD shows the reproducibility of some gene targets in vascular dementia specimens as compared to AD ones. ConclusionsThe PolyI:C model of sterile infection demonstrates that peripheral chronic inflammation causes progressive tau hyperphosphorylation, changes in microglia morphology, astrogliosis and gene reprogramming reflecting increased neuroinflammation, vascular remodeling, and the loss of neuronal functionality seen to some extent in human AD and Vascular dementia suggesting early immune insults could be crucial in neurodegenerative diseases.

Mechanistic insight into female predominance in Alzheimer's disease based on aberrant protein S-nitrosylation of C3.

Protein S-nitros(yl)ation (SNO) is a posttranslational modification involved in diverse processes in health and disease and can contribute to synaptic damage in Alzheimer's disease (AD). To identify SNO proteins in AD brains, we used triaryl phosphine (SNOTRAP) combined with mass spectrometry (MS). We detected 1449 SNO proteins with 2809 SNO sites, representing a wide range of S-nitrosylated proteins in 40 postmortem AD and non-AD human brains from patients of both sexes. Integrative protein ranking revealed the top 10 increased SNO proteins, including complement component 3 (C3), p62 (SQSTM1), and phospholipase D3. Increased levels of S-nitrosylated C3 were present in female over male AD brains. Mechanistically, we show that formation of SNO-C3 is dependent on falling β-estradiol levels, leading to increased synaptic phagocytosis and thus synapse loss and consequent cognitive decline. Collectively, we demonstrate robust alterations in the S-nitrosoproteome that contribute to AD pathogenesis in a sex-dependent manner.

An amino-terminal fragment of apolipoprotein E4 leads to behavioral deficits, increased PHF-1 immunoreactivity, and mortality in zebrafish.

Although the increased risk of developing sporadic Alzheimer's disease (AD) associated with the inheritance of the apolipoprotein E4 (APOE4) allele is well characterized, the molecular underpinnings of how ApoE4 imparts risk remains unknown. Enhanced proteolysis of the ApoE4 protein with a toxic-gain of function has been suggested and a 17 kDa amino-terminal ApoE4 fragment (nApoE41-151) has been identified in post-mortem human AD frontal cortex sections. Recently, we demonstrated in vitro, exogenous treatment of nApoE41-151 in BV2 microglial cells leads to uptake, trafficking to the nucleus and increased expression of genes associated with cell toxicity and inflammation. In the present study, we extend these findings to zebrafish (Danio rerio), an in vivo model system to assess the toxicity of nApoE41-151. Exogenous treatment of nApoE41-151 to 24-hour post-fertilization for 24 hours resulted in significant mortality. In addition, developmental abnormalities were observed following treatment with nApoE41-151 including improper folding of the hindbrain, delay in ear development, deformed yolk sac, enlarged cardiac cavity, and significantly lower heart rates. A similar nApoE31-151 fragment that differs by a single amino acid change (C>R) at position 112 had no effects on these parameters under identical treatment conditions. Decreased presence of pigmentation was noted for both nApoE31-151- and nApoE41-151-treated larvae compared with controls. Behaviorally, touch-evoked responses to stimulus were negatively impacted by treatment with nApoE41-151 but did not reach statistical significance. Additionally, triple-labeling confocal microscopy not only confirmed the nuclear localization of the nApoE41-151 fragment within neuronal populations following exogenous treatment, but also identified the presence of tau pathology, one of the hallmark features of AD. Collectively, these in vivo data demonstrating toxicity as well as sublethal effects on organ and tissue development support a novel pathophysiological function of this AD associated-risk factor.

Modulations of bioactive lipids and their receptors in postmortem Alzheimer's disease brains.

Analyses of brain samples from Alzheimer's disease (AD) patients may be expected to help us improve our understanding of the pathogenesis of AD. Bioactive lipids, including sphingolipids, glycerophospholipids, and eicosanoids/related mediators have been demonstrated to exert potent physiological actions and to be involved in the pathogenesis of various human diseases. In this cross-sectional study, we attempted to elucidate the associations of these bioactive lipids with the pathogenesis/pathology of AD through postmortem studies of human brains. We measured the levels of glycerophospholipids, sphingolipids, and eicosanoids/related mediators in the brains of patients with AD (AD brains), patients with Cerad score B (Cerad-b brains), and control subjects (control brains), using a liquid chromatography-mass spectrometry method; we also measured the mRNA levels of specific receptors for these bioactive lipids in the same brain specimens. The levels of several species of sphingomyelins and ceramides were higher in the Cerad-b and AD brains. Levels of several species of lysophosphatidic acids (LPAs), lysophosphatidylcholine, lysophosphatidylserine, lysophosphatidylethanolamine (LPE), lysophosphatidylinositol, phosphatidylcholine, phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylinositol, and phosphatidylglycerol were especially high in the Cerad-b brains, while those of lysophosphatidylglycerol (LPG) were especially high in the AD brains. Several eicosanoids, including metabolites of prostaglandin E2, oxylipins, metabolites of epoxide, and metabolites of DHA and EPA, such as resolvins, were also modulated in the AD brains. Among the lipid mediators, the levels of S1P2, S1P5, LPA1, LPA2, LPA6, P2Y10, GPR174, EP1, DP1, DP2, IP, FP, and TXA2r were lower in the AD and/or Cerad-b brains. The brain levels of ceramides, LPC, LPI, PE, and PS showed strong positive correlations with the Aβ contents, while those of LPG showed rather strong positive correlations with the presence of senile plaques and neurofibrillary tangles. A discriminant analysis revealed that LPG is especially important for AD and the LPE/PE axis is important for Cerad-b. Comprehensive lipidomics, together with the measurement of lipid receptor expression levels provided novel evidence for the associations of bioactive lipids with AD, which is expected to facilitate future translational research and reverse translational research.

TDP-43 pathology effect on volume and flortaucipir uptake in Alzheimer's disease.

Alzheimer's disease (AD) patients ≥70 years show smaller medial temporal volumes despite less 18 F-flortaucipir-positron emission tomography (PET) uptake than younger counterparts. We investigated whether TAR DNA-binding protein 43 (TDP-43) was contributing to this volume-uptake mismatch. Seventy-seven participants with flortaucipir-PET and volumetric magnetic resonance imaging underwent postmortem AD and TDP-43 pathology assessments. Bivariate-response linear regression estimated the effect of age and TDP-43 pathology on volume and/or flortaucipir standardized uptake volume ratios of the hippocampus, amygdala, entorhinal, inferior temporal, and midfrontal cortices. Older participants had lower hippocampal volumes and overall flortaucipir uptake. TDP-43-immunoreactivity correlated with reduced medial temporal volumes but was unrelated to flortaucipir uptake. TDP-43 effect size was consistent across the age spectrum. However, at older ages, the cohort mean volumes moved toward those of TDP-43-positives, reflecting the increasing TDP-43 pathology frequency with age. TDP-43 pathology is a relevant contributor driving the volume-uptake mismatch in older AD participants. TDP-43 pathology affects medial temporal volume loss but not tau radiotracer uptake. Greater TDP-43 pathology effect is seen in old age due to its increasing frequency. TDP-43 pathology is a relevant driver of the volume-uptake mismatch in old AD patients.

Dual-Specificity Protein Phosphatase 4 (DUSP4) Overexpression Improves Learning Behavior Selectively in Female 5xFAD Mice, and Reduces β-Amyloid Load in Males and Females.

Recent multiscale network analyses of banked brains from subjects who died of late-onset sporadic Alzheimer's disease converged on VGF (non-acronymic) as a key hub or driver. Within this computational VGF network, we identified the dual-specificity protein phosphatase 4 (DUSP4) [also known as mitogen-activated protein kinase (MAPK) phosphatase 2] as an important node. Importantly, DUSP4 gene expression, like that of VGF, is downregulated in postmortem Alzheimer's disease (AD) brains. We investigated the roles that this VGF/DUSP4 network plays in the development of learning behavior impairment and neuropathology in the 5xFAD amyloidopathy mouse model. We found reductions in DUSP4 expression in the hippocampi of male AD subjects, correlating with increased CDR scores, and in 4-month-old female and 12-18-month-old male 5xFAD hippocampi. Adeno-associated virus (AAV5)-mediated overexpression of DUSP4 in 5xFAD mouse dorsal hippocampi (dHc) rescued impaired Barnes maze performance in females but not in males, while amyloid loads were reduced in both females and males. Bulk RNA sequencing of the dHc from 5-month-old mice overexpressing DUSP4, and Ingenuity Pathway and Enrichr analyses of differentially expressed genes (DEGs), revealed that DUSP4 reduced gene expression in female 5xFAD mice in neuroinflammatory, interferon-gamma (IFNγ), programmed cell death protein-ligand 1/programmed cell death protein 1 (PD-L1/PD-1), and extracellular signal-regulated kinase (ERK)/MAPK pathways, via which DUSP4 may modulate AD phenotype with gender-specificity.

Differential rates of internalisation and effects on reactivity of postmortem human tau in human astrocytes

AbstractBackgroundHighly phosphorylated tau aggregates emerge in affected areas of human tauopathy brain as disease progresses as a result of prion‐like spread and/or replication of seeds. Evidence suggests that astrocytes may influence tau spread. However, the efficiency of uptake of disease‐associated tau species is not well defined, nor are the effects of tau uptake on astrocyte reactivity and function. We are investigating tau uptake in human astrocytes, and how resulting changes in their reactivity and functions affect their support for human neurons in vitro.MethodHuman iPSC‐derived astrocytes were established, and their gene and protein expression profiles characterised. Aggregated tau was isolated from human postmortem Alzheimer’s disease (AD) brain. AD brain tau and corresponding extracts from control (CTRL) human brain were spiked into iPSC‐astrocyte cultures and the efficiency of tau uptake was measured, in parallel with assessment of reactivity markers. Mechanisms of tau uptake and its intracellular processing were investigated. Astrocyte conditioned media was collected and applied to iPSC derived cortical neurons to determine the impact of tau‐induced astrocyte changes on measures of neuron health.ResultiPSC‐derived astrocytes express mature astrocyte markers. Aggregated tau from AD brain was readily internalised by these cells. Morphological, gene expression and protein expression changes were detected, suggesting that exposure to AD‐brain tau is sufficient to induce reactive response in these astrocytes. Variations in the rate and extent of uptake, and in markers of reactivity, were observed that reflect heterogeneity between different AD cases. Preliminary data indicates that cells may degrade internalised tau aggregates via lysosomal pathways and that tau‐induced astrocyte reactivity negatively impacts neuron health.ConclusionOur data shows that human astrocytes readily internalise AD brain‐derived tau aggregates, inducing changes in astrocyte reactivity and function, related to characteristics of the tau, that are detrimental to neurons. This supports an emerging body of evidence that astrocytic tau may influence neurodegeneration in AD.

Loss of Cholinergic Receptor Muscarinic 1 (CHRM1) Protein in the Hippocampus and Temporal Cortex of a Subset of Individuals with Alzheimer's Disease, Parkinson's Disease, or Frontotemporal Dementia: Implications for Patient Survival.

Dysfunction of cholinergic neurotransmission is a hallmark of Alzheimer's disease (AD); forming the basis for using acetylcholine (ACh) esterase (AChE) inhibitors to mitigate symptoms of ACh deficiency in AD. The Cholinergic Receptor Muscarinic 1 (CHRM1) is highly expressed in brain regions impaired by AD. Previous analyses of postmortem AD brains revealed unaltered CHRM1 mRNA expression compared to normal brains. However, the CHRM1 protein level in AD and other forms of dementia has not been extensively studied. Reduced expression of CHRM1 in AD patients may explain the limited clinical efficacy of AChE inhibitors. To quantify CHRM1 protein in the postmortem hippocampus and temporal cortex of AD, Parkinson's disease (PD), and frontotemporal dementia (FTD) patients. Western blotting was performed on postmortem hippocampus (N = 19/73/7/9: unaffected/AD/FTD/PD) and temporal cortex (N = 9/74/27: unaffected/AD/PD) using a validated anti-CHRM1 antibody. Quantification based on immunoblotting using a validated anti-CHRM1 antibody revealed a significant loss of CHRM1 protein level (<50%) in the hippocampi (78% AD, 66% PD, and 85% FTD) and temporal cortices (56% AD and 42% PD) of dementia patients. Loss of CHRM1 in the temporal cortex was significantly associated with early death (<65-75 years) for both AD and PD patients. Severe reduction of CHRM1 in a subset of AD and PD patients can explain the reported low efficacy of AChE inhibitors as a mitigating treatment for dementia patients. Based on this study, it can be suggested that future research should prioritize therapeutic restoration of CHRM1 protein levels in cholinergic neurons.

Cerebrovascular insulin receptors are defective in Alzheimer's disease.

Central response to insulin is suspected to be defective in Alzheimer's disease. As most insulin is secreted in the bloodstream by the pancreas, its capacity to regulate brain functions must, at least partly, be mediated through the cerebral vasculature. However, how insulin interacts with the blood-brain barrier and whether alterations of this interaction could contribute to Alzheimer's disease pathophysiology both remain poorly defined. Here, we show that human and murine cerebral insulin receptors (INSRs), particularly the long isoform INSRα-B, are concentrated in microvessels rather than in the parenchyma. Vascular concentrations of INSRα-B were lower in the parietal cortex of subjects diagnosed with Alzheimer's disease, positively correlating with cognitive scores, leading to a shift towards a higher INSRα-A/B ratio, consistent with cerebrovascular insulin resistance in the Alzheimer's disease brain. Vascular INSRα was inversely correlated with amyloid-β plaques and β-site APP cleaving enzyme 1, but positively correlated with insulin-degrading enzyme, neprilysin and P-glycoprotein. Using brain cerebral intracarotid perfusion, we found that the transport rate of insulin across the blood-brain barrier remained very low (<0.03 µl/g·s) and was not inhibited by an insulin receptor antagonist. However, intracarotid perfusion of insulin induced the phosphorylation of INSRβ that was restricted to microvessels. Such an activation of vascular insulin receptor was blunted in 3xTg-AD mice, suggesting that Alzheimer's disease neuropathology induces insulin resistance at the level of the blood-brain barrier. Overall, the present data in post-mortem Alzheimer's disease brains and an animal model of Alzheimer's disease indicate that defects in the insulin receptor localized at the blood-brain barrier strongly contribute to brain insulin resistance in Alzheimer's disease, in association with β-amyloid pathology.

Comparative analysis of transcriptome remodeling in plaque-associated and plaque-distant microglia during amyloid-β pathology progression in mice

BackgroundResearch in recent years firmly established that microglial cells play an important role in the pathogenesis of Alzheimer's disease (AD). In parallel, a series of studies showed that, under both homeostatic and pathological conditions, microglia are a heterogeneous cell population. In AD, amyloid-β (Aβ) plaque-associated microglia (PAM) display a clearly distinct phenotype compared to plaque-distant microglia (PCM), suggesting that these two microglia subtypes likely differently contribute to disease progression. So far, molecular characterization of PAM was performed indirectly using single cell RNA sequencing (scRNA-seq) approaches or based on markers that are supposedly up-regulated in this microglia subpopulation.MethodsIn this study based on a well-characterized AD mouse model, we combined cell-specific laser capture microdissection and RNA-seq analysis to i) identify, without preconceived notions of the molecular and/or functional changes that would affect these cells, the genes and gene networks that are dysregulated in PAM or PCM at three critical stages of the disease, and ii) to investigate the potential contribution of both plaque-associated and plaque-distant microglia.ResultsFirst, we established that our approach allows selective isolation of microglia, while preserving spatial information and preventing transcriptome changes induced by classical purification approaches. Then, we identified, in PAM and PCM subpopulations, networks of co-deregulated genes and analyzed their potential functional roles in AD. Finally, we investigated the dynamics of microglia transcriptomic remodeling at early, intermediate and late stages of the disease and validated select findings in postmortem human AD brain.ConclusionsOur comprehensive study provides useful transcriptomic information regarding the respective contribution of PAM and PCM across the Aβ pathology progression. It highlights specific pathways that would require further study to decipher their roles across disease progression. It demonstrates that the proximity of microglia to Aβ-plaques dramatically alters the microglial transcriptome and reveals that these changes can have both positive and negative impacts on the surrounding cells. These opposing effects may be driven by local microglia heterogeneity also demonstrated by this study. Our approach leads to molecularly define the less well studied plaque-distant microglia. We show that plaque-distant microglia are not bystanders of the disease, although the transcriptomic changes are far less striking compared to what is observed in plaque-associated microglia. In particular, our results suggest they may be involved in Aβ oligomer detection and in Aβ-plaque initiation, with increased contribution as the disease progresses.Graphical

Olfactory Dysfunction and Incidence of Motoric Cognitive Risk Syndrome: A Prospective Clinical-Pathologic Study.

To examine associations between olfactory dysfunction, Alzheimer disease (AD) pathology, and motoric cognitive risk syndrome (MCR), a predementia syndrome characterized by cognitive complaints and slow gait that is associated with risk for AD and other dementias. We conducted a retrospective analysis of a prospective cohort study to examine whether baseline olfactory function was associated with the risk of incident MCR in 1,119 adults aged 60 years and older (75.1% female). The association between performance on the Brief Smell Identification Test (BSIT) and incident MCR risk was computed using Cox models and reported as the hazard ratio (HR) with 95% CIs adjusted for demographic, comorbidity, and cognitive factors. Furthermore, we assessed the relationship between postmortem AD pathology and non-AD pathology and olfactory function at the time of MCR diagnosis using linear regression models adjusted for sex, education, age at death, and time from diagnosis to death. There were 544 (48.6%) incident cases of MCR over a median follow-up of 3.94 years. Lower BSIT scores (poor olfaction) at baseline were associated with an increased risk of incident MCR (HR for a 1-point increase in BSIT score 0.92; 95% CI 0.88-0.96) in fully adjusted models. Those with hyposmia (scores of ≤8 on the BSIT) at baseline (26.6%) were at an increased risk of MCR (HR 1.44; 95% CI 1.19-1.74) compared with those with normal olfactory function. Higher levels of the composite measure of global AD pathology and presence of Lewy body pathology were associated with lower BSIT scores at the time of incident MCR diagnosis (n = 118). τ tangle density, a specific component of AD pathology, was inversely associated with olfactory function, and the correlation remained after controlling for mild cognitive impairment syndrome and the presence of Lewy body pathology. The results provide evidence that olfactory dysfunction precedes MCR incidence and is related to Alzheimer pathology, providing a clinical approach to risk stratify and subtype MCR.

USP10 deubiquitinates Tau, mediating its aggregation

Normal Tau promotes the assembly and stabilization of microtubules, thus, maintaining axon transport. In Alzheimer’s disease (AD), Tau aggregation causes it to lose these above-mentioned functions. However, the molecular mechanism leading to Tau aggregation in AD remains ambiguous. Here, we report that USP10, one of the important deubiquitinases (DUBs), is involved in Tau aggregation. We found that USP10 is upregulated in postmortem human AD and APP/PS1 mice brains, but not in P301S mice brains. Moreover, in primary neuronal cultures, Aβ42 induces a dose-dependent USP10 upregulation, an increase in the levels of both total and phosphorylated Tau, as well as a markedly elevated Tau binding with USP10, that is accompanied by a significantly decreased Tau ubiquitination. In addition, overexpression of USP10 directly causes an increase in the levels of total and phosphorylated Tau, induces Tau aggregation, and delays in Tau degradation. Results from mass spectrometry, reciprocal immunoprecipitation, and immunofluorescence assays strongly prove Tau’s interaction with USP10. This is further supported by the Tau307–326K and Tau341–378K peptides’ competitive inhibition of Tau binding with USP10, attenuating Tau hyperphosphorylation and Tau deubiquitination. Together, our data strongly indicate that USP10 plays a critical role in mediating Tau aggregation via downregulating its ubiquitination and thus slowing down Tau turnover. Inhibition of USP10-Tau interaction might be therapeutically useful in the management of AD and related tauopathies.

Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation

Tau protein aggregates are a major driver of neurodegeneration and behavioral impairments in tauopathies, including in Alzheimer's disease (AD). Apolipoprotein E4 (APOE4), the highest genetic risk factor for late-onset AD, has been shown to exacerbate tau hyperphosphorylation in mouse models. However, the exact mechanisms through which APOE4 induces tau hyperphosphorylation remains unknown. Here, we report that the astrocyte-secreted protein glypican-4 (GPC-4), which we identify as a binding partner of APOE4, drives tau hyperphosphorylation. We discovered that first, GPC-4 preferentially interacts with APOE4 in comparison to APOE2, considered to be a protective allele to AD, and second, that postmortem APOE4-carrying AD brains highly express GPC-4 in neurotoxic astrocytes. Furthermore, the astrocyte-secreted GPC-4 induced both tau accumulation and propagation invitro. CRISPR/dCas9-mediated activation of GPC-4 in a tauopathy mouse model robustly induced tau hyperphosphorylation. In the absence of GPC4, APOE4-induced tau hyperphosphorylation was largely diminished using invitro tau fluorescence resonance energy transfer-biosensor cells, in human-induced pluripotent stem cell-derived astrocytes and in an invivo mouse model. We further show that APOE4-mediated surface trafficking of APOE receptor low-density lipoprotein receptor-related protein 1 through GPC-4 can be a gateway to tau spreading. Collectively, these data support that APOE4-induced tau hyperphosphorylation is directly mediated by GPC-4.

APOE ε4 and Alzheimer's disease diagnosis associated differences in L-carnitine, GBB, TMAO, and acylcarnitines in blood and brain

The apolipoprotein E (APOE) ε4 allele, involved in fatty acid (FA) metabolism, is a major genetic risk factor for Alzheimer's disease (AD). This study examined the influence of APOE genotypes on blood and brain markers of the L-carnitine system, necessary for fatty acid oxidation (FAO), and their collective influence on the clinical and pathological outcomes of AD. L-carnitine, its metabolites γ-butyrobetaine (GBB) and trimethylamine-n-oxide (TMAO), and its esters (acylcarnitines) were analyzed in blood from predominantly White community/clinic-based individuals (n = 372) and in plasma and brain from the Religious Order Study (ROS) (n = 79) using liquid chromatography tandem mass spectrometry (LC-MS/MS). Relative to total blood acylcarnitines, levels of short chain acylcarnitines (SCAs) were higher whereas long chain acylcarnitines (LCAs) were lower in AD, which was observed pre-clinically in APOE ε4s. Plasma medium chain acylcarnitines (MCAs) were higher amongst cognitively healthy APOE ε2 carriers relative to other genotypes. Compared to their respective controls, elevated TMAO and lower L-carnitine and GBB were associated with AD clinical diagnosis and these differences were detected preclinically among APOE ε4 carriers. Plasma and brain GBB, TMAO, and acylcarnitines were also associated with post-mortem brain amyloid, tau, and cerebrovascular pathologies. Alterations in blood L-carnitine, GBB, TMAO, and acylcarnitines occur early in clinical AD progression and are influenced by APOE genotype. These changes correlate with post-mortem brain AD and cerebrovascular pathologies. Additional studies are required to better understand the role of the FAO disturbances in AD.

Corpora amylacea are associated with tau burden and cognitive status in Alzheimer’s disease

Corpora amylacea (CA) and their murine analogs, periodic acid Schiff (PAS) granules, are age-related, carbohydrate-rich structures that serve as waste repositories for aggregated proteins, damaged cellular organelles, and other cellular debris. The structure, morphology, and suspected functions of CA in the brain imply disease relevance. Despite this, the link between CA and age-related neurodegenerative diseases, particularly Alzheimer’s disease (AD), remains poorly defined. We performed a neuropathological analysis of mouse PAS granules and human CA and correlated these findings with AD progression. Increased PAS granule density was observed in symptomatic tau transgenic mice and APOE knock-in mice. Using a cohort of postmortem AD brain samples, we examined CA in cognitively normal and dementia patients across Braak stages with varying APOE status. We identified a Braak-stage dependent bimodal distribution of CA in the dentate gyrus, with CA accumulating and peaking by Braak stages II–III, then steadily declining with increasing tau burden. Refined analysis revealed an association of CA levels with both cognition and APOE status. Finally, tau was detected in whole CA present in human patient cerebrospinal fluid, highlighting CA-tau as a plausible prodromal AD biomarker. Our study connects hallmarks of the aging brain with the emergence of AD pathology and suggests that CA may act as a compensatory factor that becomes depleted with advancing tau burden.

Selective Detection of Misfolded Tau From Postmortem Alzheimer's Disease Brains.

Tau aggregates are present in multiple neurodegenerative diseases known as “tauopathies,” including Alzheimer’s disease, Pick’s disease, progressive supranuclear palsy, and corticobasal degeneration. Such misfolded tau aggregates are therefore potential sources for selective detection and biomarker discovery. Six human tau isoforms present in brain tissues and both 3R and 4R isoforms have been observed in the neuronal inclusions. To develop selective markers for AD and related rare tauopathies, we first used an engineered tau protein fragment 4RCF as the substrate for ultrasensitive real-time quaking-induced conversion analyses (RT-QuIC). We showed that misfolded tau from diseased AD and other tauopathy brains were able to seed recombinant 4RCF substrate. We further expanded to use six individual recombinant tau isoforms as substrates to amplify misfolded tau seeds from AD brains. We demonstrated, for the first time to our knowledge, that misfolded tau from the postmortem AD brain tissues was able to specifically seed all six full-length human tau isoforms. Our results demonstrated that RT-QuIC analysis can discriminate AD and other tauopathies from non-AD normal controls. We further uncovered that 3R-tau isoforms displayed significantly faster aggregation kinetics than their 4R-tau counterparts under conditions of both no seeding and seeding with AD brain homogenates. In summary, our work offers potential new avenues of misfolded tau detection as potential biomarkers for diagnosis of AD and related tauopathies and provides new insights into isoform-specific human tau aggregation.

124I]IBETA: A New Aβ Plaque Positron Emission Tomography Imaging Agent for Alzheimer's Disease.

Several fluorine-18-labeled PET β-amyloid (Aβ) plaque radiotracers for Alzheimer’s disease (AD) are in clinical use. However, no radioiodinated imaging agent for Aβ plaques has been successfully moved forward for either single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. Radioiodinated pyridyl benzofuran derivatives for the SPECT imaging of Aβ plaques using iodine-123 and iodine-125 are being pursued. In this study, we assess the iodine-124 radioiodinated pyridyl benzofuran derivative 5-(5-[124I]iodobenzofuran-2-yl)-N,N-dimethylpyridin-2-amine ([124I]IBETA) (Ki = 2.36 nM) for utilization in PET imaging for Aβ plaques. We report our findings on the radioiododestannylation reaction used to prepare [124/125I]IBETA and evaluate its binding to Aβ plaques in a 5 × FAD mouse model and postmortem human AD brain. Both [125I]IBETA and [124I]IBETA are produced in >25% radiochemical yield and >85% radiochemical purity. The in vitro binding of [125I]IBETA and [124I]IBETA in transgenic 5 × FAD mouse model for Aβ plaques was high in the frontal cortex, anterior cingulate, thalamus, and hippocampus, which are regions of high Aβ accumulation, with very little binding in the cerebellum (ratio of brain regions to cerebellum was >5). The in vitro binding of [125I]IBETA and [124I]IBETA in postmortem human AD brains was higher in gray matter containing Aβ plaques compared to white matter (ratio of gray to white matter was >5). Anti-Aβ immunostaining strongly correlated with [124/125I]IBETA regional binding in both the 5 × FAD mouse and postmortem AD human brains. The binding of [124/125I]IBETA in 5 × FAD mouse and postmortem human AD brains was displaced by the known Aβ plaque imaging agent, Flotaza. Preliminary PET/CT studies of [124I]IBETA in the 5 × FAD mouse model suggested [124I]IBETA was relatively stable in vivo with a greater localization of [124I]IBETA in the brain regions with a high concentration of Aβ plaques. Some deiodination was observed at later time points. Therefore, [124I]IBETA may potentially be a useful PET radioligand for Aβ plaques in brain studies.

A partial reduction of VDAC1 enhances mitophagy, autophagy, synaptic activities in a transgenic Tau mouse model.

Alzheimer's disease (AD) is the most common cause of mental dementia in the aged population. AD is characterized by the progressive decline of memory and multiple cognitive functions, and changes in behavior and personality. Recent research has revealed age‐dependent increased levels of VDAC1 in postmortem AD brains and cerebral cortices of APP, APPxPS1, and 3xAD.Tg mice. Further, we found abnormal interaction between VDAC1 and P‐Tau in the AD brains, leading to mitochondrial structural and functional defects. Our current study aimed to understand the impact of a partial reduction of voltage‐dependent anion channel 1 (VDAC1) protein on mitophagy/autophagy, mitochondrial and synaptic activities, and behavior changes in transgenic TAU mice in Alzheimer's disease. To determine if a partial reduction of VDAC1 reduces mitochondrial and synaptic toxicities in transgenic Tau (P301L) mice, we crossed heterozygote VDAC1 knockout (VDAC1+/−) mice with TAU mice and generated double mutant (VDAC1+/−/TAU) mice. We assessed phenotypic behavior, protein levels of mitophagy, autophagy, synaptic, other key proteins, mitochondrial morphology, and dendritic spines in TAU mice relative to double mutant mice. Partial reduction of VDAC1 rescued the TAU‐induced behavioral impairments such as motor coordination and exploratory behavioral changes, and learning and spatial memory impairments in VDAC1+/−/TAU mice. Protein levels of mitophagy, autophagy, and synaptic proteins were significantly increased in double mutant mice compared with TAU mice. In addition, dendritic spines were significantly increased; the mitochondrial number was significantly reduced, and mitochondrial length was increased in double mutant mice. Based on these observations, we conclude that reduced VDAC1 is beneficial in symptomatic‐transgenic TAU mice.

The Role of Human Herpesvirus 6 Infection in Alzheimer's Disease Pathogenicity-A Theoretical Mosaic.

Alzheimer’s disease (AD), a neurodegenerative disorder generally affecting older adults, is the most common form of dementia worldwide. The disease is marked by severe cognitive and psychiatric decline and has dramatic personal and social consequences. Considerable time and resources are dedicated to the pursuit of a better understanding of disease mechanisms; however, the ultimate goal of obtaining a viable treatment option remains elusive. Neurodegenerative disease as an outcome of gene–environment interaction is a notion widely accepted today; a clear understanding of how external factors are involved in disease pathogenesis is missing, however. In the case of AD, significant effort has been invested in the study of viral pathogens and their role in disease mechanisms. The current scoping review focuses on the purported role HHV-6 plays in AD pathogenesis. First, early studies demonstrating evidence of HHV-6 cantonment in either post-mortem AD brain specimens or in peripheral blood samples of living AD patients are reviewed. Next, selected examples of possible mechanisms whereby viral infection can directly or indirectly contribute to AD pathogenesis are presented, such as autophagy dysregulation, the interaction between miR155 and HHV-6, and amyloid-beta as an antimicrobial peptide. Finally, closely related topics such as HHV-6 penetration in the CNS, HHV-6 involvement in neuroinflammation, and a brief discussion on HHV-6 epigenetics are examined.

Mixed Cerebrovascular And Alzheimer’s Type Pathology Mimicking Lewy Body Disease And Its Possible Contribution To the Increased Risk of Developing Cognitive Impairment In Elderly Patients with Bipolar Disorder/Schizophrenia

BackgroundIt has been recently reported that bipolar disorder (BD), as compared to other major adult psychiatric disorders, was associated with an increased risk of developing Parkinson’s disease (PD), cerebrovascular disease (CVD), and dementia in a later life (PMID: 33075191). The similar to BD increased risk of developing dementia was also observed for schizophrenia (SCZ) (PMID: 33075191). Surprisingly, the most common cause of dementia, Alzheimer’s disease (AD) (PMID: 31564456), was absent in elderly BD patients with cognitive impairment when AD was probed by its signature biomarkers in the cerebrospinal fluid (PMID: 26876913). Altogether, these data question AD contribution to the increased risk for dementia development in elderly patients with BD. Therefore, the main objective of this study was to address the above issue by probing postmortem AD related pathology in two brains of 83‐year‐old individuals. The first subject (D1) was diagnosed with BD, SCZ, and PD, whereas the second (D2) had Lewy Body Dementia (LBD). PD, PD dementia, and LBD constitute Lewy Body Disease (PMID: 30665447).ResultsParaffin embedded tissue sections from specific regions of each brain underwent H&amp;E staining, as well as immunohistochemical staining for β‐amyloid and phospho‐tau. Upon examination, Lewy bodies were not observed in D1 and D2 brains and the substantia nigra was well preserved in both brains, thereby not confirming the respective PD and LBD diagnoses. However, D1 brain displayed Alzheimer’s type pathology in the frontal, temporal, and occipital cortices as well as in the hippocampus. The respective pathological features included senile plaques and neurofibrillary tangles (NFTs) in the cortices and hippocampus as well as granulovacuolar degeneration (GVD) in pyramidal neurons of the hippocampus. Interestingly, in the same brain, a strong diffused β‐amyloid staining of potential significance was observed within the cerebellar neurons. Overall, the severity of the respective Alzheimer’s type pathology in D1 brain could be characterized by its clinical stage as mild to moderate. Importantly, there were also vascular changes in D1 brain consistent with hypertensive CVD including hyaline atherosclerosis, microbleeds, and dilated Virchow Robin spaces. Some blood vessels showed β‐amyloid deposits within the vessel wall and lumen which is indicative of amyloid angiopathy. In D2 brain, the AD pathology was also present in the form of NFTs and GVD in the hippocampus and was accompanied by mild neuronal loss in the hippocampus and cortex. Striking vascular pathology including thick‐walled blood vessels with microbleeds was also observed.Conclusionsi) AD could be present in elderly BD/SCZ patients and advance to clinical stage associated with cognitive impairment. ii) CVD in conjunction with AD could mimic Lewy Body Disease and contribute to the increased risk of dementia development in older BD/SCZ patients. iii) A proper diagnosis of dementia associated with mixed CVD/AD pathology in elderly patients with BD/SCZ would be important for their adequate treatment and care.