Novel inductively coupled ear-bars (ICEs) to enhance restored fMRI signal from susceptibility compensation in rats.

Functional magnetic resonance imaging faces inherent challenges when applied to deep-brain areas in rodents, e.g. entorhinal cortex, due to the signal loss near the ear cavities induced by susceptibility artifacts and reduced sensitivity induced by the long distance from the surface array coil. Given the pivotal roles of deep brain regions in various diseases, optimized imaging techniques are needed. To mitigate susceptibility-induced signal losses, we introduced baby cream into the middle ear. To enhance the detection sensitivity of deep brain regions, we implemented inductively coupled ear-bars, resulting in approximately a 2-fold increase in sensitivity in entorhinal cortex. Notably, the inductively coupled ear-bar can be seamlessly integrated as an add-on device, without necessitating modifications to the scanner interface. To underscore the versatility of inductively coupled ear-bars, we conducted echo-planner imaging-based task functional magnetic resonance imaging in rats modeling Alzheimer's disease. As a proof of concept, we also demonstrated resting-state-functional magnetic resonance imaging connectivity maps originating from the left entorhinal cortex-a central hub for memory and navigation networks-to amygdala hippocampal area, Insular Cortex, Prelimbic Systems, Cingulate Cortex, Secondary Visual Cortex, and Motor Cortex. This work demonstrates an optimized procedure for acquiring large-scale networks emanating from a previously challenging seed region by conventional magnetic resonance imaging detectors, thereby facilitating improved observation of functional magnetic resonance imaging outcomes.

Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA), updates in 2022-2023. Cerebrovascular disease and the failure of elimination of Amyloid-ß from the brain and retina with age and Alzheimer's disease: Opportunities for therapy.

This editorial summarizes advances from the Clearance of Interstitial Fluid and Cerebrospinal Fluid (CLIC) group, within the Vascular Professional Interest Area (PIA) of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART). The overarching objectives of the CLIC group are to: (1) understand the age-related physiology changes that underlie impaired clearance of interstitial fluid (ISF) and cerebrospinal fluid (CSF) (CLIC); (2) understand the cellular and molecular mechanisms underlying intramural periarterial drainage (IPAD) in the brain; (3) establish novel diagnostic tests for Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), retinal amyloid vasculopathy, amyloid-related imaging abnormalities (ARIA) of spontaneous and iatrogenic CAA-related inflammation (CAA-ri), and vasomotion; and (4) establish novel therapies that facilitate IPAD to eliminate amyloid ß (Aß) from the aging brain and retina, to prevent or reduce AD and CAA pathology and ARIA side events associated with AD immunotherapy.

Human microRNA (miR-20b-5p) modulates Alzheimer's disease pathways and neuronal function, and a specific polymorphism close to the MIR20B gene influences Alzheimer's biomarkers.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with loss of cognitive, executive, and other mental functions, and is the most common form of age-related dementia. Amyloid-ß peptide (Aß) contributes to the etiology and progression of the disease. Aß is derived from the amyloid-ß precursor protein (APP). Multiple microRNA (miRNA) species are also implicated in AD. We report that human hsa-miR20b-5p (miR-20b), produced from the MIR20B gene on Chromosome X, may play complex roles in AD pathogenesis, including Aß regulation. Specifically, miR-20b-5p miRNA levels were altered in association with disease progression in three regions of the human brain: temporal neocortex, cerebellum, and posterior cingulate cortex. In cultured human neuronal cells, miR-20b-5p treatment interfered with calcium homeostasis, neurite outgrowth, and branchpoints. A single-nucleotide polymorphism (SNP) upstream of the MIR20B gene (rs13897515) associated with differences in levels of cerebrospinal fluid (CSF) Aß1-42 and thickness of the entorhinal cortex. We located a miR-20b-5p binding site in the APP mRNA 3'-untranslated region (UTR), and treatment with miR-20b-5p reduced APP mRNA and protein levels. Network analysis of protein-protein interactions and gene coexpression revealed other important potential miR-20b-5p targets among AD-related proteins/genes. MiR-20b-5p, a miRNA that downregulated APP, was paradoxically associated with an increased risk for AD. However, miR-20b-5p also reduced, and the blockade of APP by siRNA likewise reduced calcium influx. As APP plays vital roles in neuronal health and does not exist solely to be the source of "pathogenic" Aß, the molecular etiology of AD is likely to not just be a disease of "excess" but a disruption of delicate homeostasis.

Enhancing mitochondrial proteostasis reduces amyloid-ß proteotoxicity.

Alzheimer's disease is a common and devastating disease characterized by aggregation of the amyloid-ß peptide. However, we know relatively little about the underlying molecular mechanisms or how to treat patients with Alzheimer's disease. Here we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in diseases involving amyloid-ß proteotoxicity in human, mouse and Caenorhabditis elegans that involves the mitochondrial unfolded protein response and mitophagy pathways. Using a worm model of amyloid-ß proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed that the induction of this mitochondrial stress response was essential for the maintenance of mitochondrial proteostasis and health. Notably, increasing mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases the fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms and in transgenic mouse models of Alzheimer's disease. Our data support the relevance of enhancing mitochondrial proteostasis to delay amyloid-ß proteotoxic diseases, such as Alzheimer's disease.

Co-expression network analysis of frontal cortex during the progression of Alzheimer's disease.

Mechanisms of Alzheimer's disease (AD) and its putative prodromal stage, amnestic mild cognitive impairment (aMCI), involve the dysregulation of multiple candidate molecular pathways that drive selective cellular vulnerability in cognitive brain regions. However, the spatiotemporal overlap of markers for pathway dysregulation in different brain regions and cell types presents a challenge for pinpointing causal versus epiphenomenal changes characterizing disease progression. To approach this problem, we performed Weighted Gene Co-expression Network Analysis and STRING interactome analysis of gene expression patterns quantified in frontal cortex samples (Brodmann area 10) from subjects who died with a clinical diagnosis of no cognitive impairment, aMCI, or mild/moderate AD. Frontal cortex was chosen due to the relatively protracted involvement of this region in AD, which might reveal pathways associated with disease onset. A co-expressed network correlating with clinical diagnosis was functionally associated with insulin signaling, with insulin (INS) being the most highly connected gene within the network. Co-expressed networks correlating with neuropathological diagnostic criteria (e.g., NIA-Reagan Likelihood of AD) were associated with platelet-endothelium-leucocyte cell adhesion pathways and hypoxia-oxidative stress. Dysregulation of these functional pathways may represent incipient alterations impacting disease progression and the clinical presentation of aMCI and AD.

Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART.

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

MicroRNA-298 reduces levels of human amyloid-ß precursor protein (APP), ß-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties.

Alzheimer's disease (AD) is the most common age-related form of dementia, associated with deposition of intracellular neuronal tangles consisting primarily of hyperphosphorylated microtubule-associated protein tau (p-tau) and extracellular plaques primarily comprising amyloid- ß (Aß) peptide. The p-tau tangle unit is a posttranslational modification of normal tau protein. Aß is a neurotoxic peptide excised from the amyloid-ß precursor protein (APP) by ß-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. MicroRNAs (miRNAs) are short, single-stranded RNAs that modulate protein expression as part of the RNA-induced silencing complex (RISC). We identified miR-298 as a repressor of APP, BACE1, and the two primary forms of Aß (Aß40 and Aß42) in a primary human cell culture model. Further, we discovered a novel effect of miR-298 on posttranslational levels of two specific tau moieties. Notably, miR-298 significantly reduced levels of ~55 and 50 kDa forms of the tau protein without significant alterations of total tau or other forms. In vivo overexpression of human miR-298 resulted in nonsignificant reduction of APP, BACE1, and tau in mice. Moreover, we identified two miR-298 SNPs associated with higher cerebrospinal fluid (CSF) p-tau and lower CSF Aß42 levels in a cohort of human AD patients. Finally, levels of miR-298 varied in postmortem human temporal lobe between AD patients and age-matched non-AD controls. Our results suggest that miR-298 may be a suitable target for AD therapy.

Anti-fibrillization effects of sulfonamide derivatives on α-synuclein and hyperphosphorylated tau isoform 1N4R.

In contrast to Aß plaques, the spatiotemporal distribution of neurofibrillary tangles of hyperphosphorylated tau (p-tau) predicts cognitive impairment in Alzheimer's disease (AD), underscoring the key pathological role of p-tau and the utmost need to develop AD therapeutics centering upon the control of p-tau aggregation and cytotoxicity. Our drug discovery program is focused on compounds that prevent the aggregation and cytotoxicity of p-tau moieties of the tau isoform 1N4R due to its prevalence (1 N) and long-distance trans-synaptic propagation (4R). We prepared and tested twenty-four newly synthesized small molecules representing the urea (1, 2, 3), sulfonylurea (4), and sulfonamide (5-24) series and evaluated their anti-aggregation effects with biophysical methods (thioflavin T and S fluorescence assays, transmission electron microscopy) and intracellular inclusion cell-based assays. Pre-evaluation was performed on alpha-synuclein (α-syn) to identify molecules to be challenged with p-tau. The sulfonamide derivatives 18 and 20 exhibited an anti-fribrillization activity on α-syn and p-tau. Sulfonamide compounds 18 and 20 reduced inclusion formation in M17D neuroblastoma cells that express inclusion-prone αSynuclein3K::YFP. This project advances new concepts in targeting prone-to-aggregate proteins such as α-syn and p-tau, and provides a molecular scaffold for further optimization and pre-clinical studies focused on AD drug development.

Brain-derived neurotrophic factor (BDNF) and TrkB hippocampal gene expression are putative predictors of neuritic plaque and neurofibrillary tangle pathology.

INTRODUCTION: Downregulation of brain-derived neurotrophic factor (BDNF) and its cognate neurotrophin receptor, TrkB, were observed during the progression of dementia, but whether the Alzheimer's disease (AD) pathological lesions diffuse plaques, (DPs), neuritic plaques (NPs), and neurofibrillary tangles (NFTs) are related to this alteration remains to be clarified. METHODS: Negative binomial (NB) regressions were performed using gene expression data accrued from a single population of CA1 pyramidal neurons and regional hippocampal dissections obtained from participants in the Rush Religious Orders Study (RROS). RESULTS: Downregulation of Bdnf is independently associated with increased entorhinal cortex NPs. Downregulation of TrkB is independently associated with increased entorhinal cortex NFTs and CA1 NPs during the progression of AD. DISCUSSION: Results indicate that BDNF and TrkB dysregulation contribute to AD neuropathology, most notably hippocampal NPs and NFTs. These data suggest attenuating BDNF/TrkB signaling deficits either at the level of BDNF, TrkB, or downstream of TrkB signaling may abrogate NPs and/or NFTs.

Selective decline of neurotrophin and neurotrophin receptor genes within CA1 pyramidal neurons and hippocampus proper: Correlation with cognitive performance and neuropathology in mild cognitive impairment and Alzheimer's disease.

Hippocampal CA1 pyramidal neurons, a major component of the medial temporal lobe memory circuit, are selectively vulnerable during the progression of Alzheimer's disease (AD). The cellular mechanism(s) underlying degeneration of these neurons and the relationship to cognitive performance remains largely undefined. Here, we profiled neurotrophin and neurotrophin receptor gene expression within microdissected CA1 neurons along with regional hippocampal dissections from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or AD using laser capture microdissection (LCM), custom-designed microarray analysis, and qPCR of CA1 subregional dissections. Gene expression levels were correlated with cognitive test scores and AD neuropathology criteria. We found a significant downregulation of several neurotrophin genes (e.g., Gdnf, Ngfb, and Ntf4) in CA1 pyramidal neurons in MCI compared to NCI and AD subjects. In addition, the neurotrophin receptor transcripts TrkB and TrkC were decreased in MCI and AD compared to NCI. Regional hippocampal dissections also revealed select neurotrophic gene dysfunction providing evidence for vulnerability within the hippocampus proper during the progression of dementia. Downregulation of several neurotrophins of the NGF family and cognate neurotrophin receptor (TrkA, TrkB, and TrkC) genes correlated with antemortem cognitive measures including the Mini-Mental State Exam (MMSE), a composite global cognitive score (GCS), and Episodic, Semantic, and Working Memory, Perceptual Speed, and Visuospatial domains. Significant correlations were found between select neurotrophic expression downregulation and neuritic plaques (NPs) and neurofibrillary tangles (NFTs), but not diffuse plaques (DPs). These data suggest that dysfunction of neurotrophin signaling complexes have profound negative sequelae within vulnerable hippocampal cell types, which play a role in mnemonic and executive dysfunction during the progression of AD.

Pretangle pathology within cholinergic nucleus basalis neurons coincides with neurotrophic and neurotransmitter receptor gene dysregulation during the progression of Alzheimer's disease.

Cholinergic basal forebrain neurons of the nucleus basalis of Meynert (nbM) regulate attentional and memory function and are exquisitely prone to tau pathology and neurofibrillary tangle (NFT) formation during the progression of Alzheimer's disease (AD). nbM neurons require the neurotrophin nerve growth factor (NGF), its cognate receptor TrkA, and the pan-neurotrophin receptor p75NTR for their maintenance and survival. Additionally, nbM neuronal activity and cholinergic tone are regulated by the expression of nicotinic (nAChR) and muscarinic (mAChR) acetylcholine receptors as well as receptors modulating glutamatergic and catecholaminergic afferent signaling. To date, the molecular and cellular relationships between the evolution of tau pathology and nbM neuronal survival remain unknown. To address this knowledge gap, we profiled cholinotrophic pathway genes within nbM neurons immunostained for pS422, a pretangle phosphorylation event preceding tau C-terminal truncation at D421, or dual-labeled for pS422 and TauC3, a later stage tau neo-epitope revealed by this same C-terminal truncation event, via single-population custom microarray analysis. nbM neurons were obtained from postmortem tissues from subjects who died with an antemortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild/moderate AD. Quantitative analysis revealed significant downregulation of mRNAs encoding TrkA as well as TrkB, TrkC, and the Trk-mediated downstream pro-survival kinase Akt in pS422+ compared to unlabeled, pS422-negative nbM neurons. In addition, pS422+ neurons displayed a downregulation of transcripts encoding NMDA receptor subunit 2B, metabotropic glutamate receptor 2, D2 dopamine receptor, and ß1 adrenoceptor. By contrast, transcripts encoding p75NTR were downregulated in dual-labeled pS422+/TauC3+ neurons. Appearance of the TauC3 epitope was also associated with an upregulation of the α7 nAChR subunit and differential downregulation of the ß2 nAChR subunit. Notably, we found that gene expression patterns for each cell phenotype did not differ with clinical diagnosis. However, linear regression revealed that global cognition and Braak stage were predictors of select transcript changes within both unlabeled and pS422+/TauC3- neurons. Taken together, these cell phenotype-specific gene expression profiling data suggest that dysregulation of neurotrophic and neurotransmitter signaling is an early pathogenic mechanism associated with NFT formation in vulnerable nbM neurons and cognitive decline in AD, which may be amenable to therapeutic intervention early in the disease process.

Vascular cognitive impairment and dementia.

Vascular contributions to cognitive impairment are receiving heightened attention as potentially modifiable factors for dementias of later life. These factors have now been linked not only to vascular cognitive disorders but also Alzheimer's disease. In this chapter we review 3 related topics that address vascular contributions to cognitive impairment: 1. vascular pathogenesis and mechanisms; 2. neuropsychological and neuroimaging phenotypic manifestations of cerebrovascular disease; and 3. prospects for prevention of cognitive impairment of later life based on cardiovascular and stroke risk modification. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

Intravenous immunoglobulin (IVIG) treatment exerts antioxidant and neuropreservatory effects in preclinical models of Alzheimer's disease.

Intravenous immunoglobulin (IVIG) has shown limited promise so far in human clinical studies on Alzheimer's disease (AD), yet overwhelmingly positive preclinical work in animals and human brain cultures support the notion that the therapy remains potentially efficacious. Here, we elaborate on IVIG neuropreservation by demonstrating that IVIG protects human primary neurons against oxidative stress in vitro and that IVIG preserves antioxidant defense mechanisms in vivo. Based on these results, we propose the following translational impact: If the dosage and treatment conditions are adequately optimized, then IVIG treatment could play a significant role in preventing and/or delaying the progression of neurodegenerative diseases, such as AD. We suggest that IVIG warrants further investigation to fully exploit its potential as an anti-oxidant, neuroprotective and synapto-protecting agent.

The seeds of its regulation: Natural antisense transcripts as single-gene control switches in neurodegenerative disorders.

Several proteins play critical roles in vulnerability or resistance to neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and frontotemporal dementia (FTD). Regulation of these proteins is critical to maintaining healthy neurohomeostasis. In addition to transcription factors regulating gene transcription and microRNAs regulating mRNA translation, natural antisense transcripts (NATs) regulate mRNA levels, splicing, and translation. NATs' roles are significant in regulating key protein-coding genes associated with neurodegenerative disorders. Elucidating the functions of these NATs could prove useful in treating or preventing diseases. NAT activity is not restricted to mRNA translation; it can also regulate DNA (de)methylation and other gene expression steps. NATs are noncoding RNAs (ncRNAs) encoded by DNA sequences overlapping the pertinent protein genes. These NATs have complex structures, including introns and exons, and therefore bind their target genes, precursor mRNAs (pre-mRNAs), and mature RNAs. They can occur at the 5'- or 3'-ends of a mRNA-coding sequence or internally to a parent gene. NATs can downregulate translation, e.g., microtubule-associated protein tau (MAPT) antisense-1 gene (MAPT-AS1), or upregulate translation, e.g., ß-Amyloid site Cleaving Enzyme 1 (BACE1) antisense gene (BACE1-AS). Regulation of NATs can parallel pathogenesis, wherein a "pathogenic" NAT (e.g., BACE1-AS) is upregulated under pathogenic conditions, while a "protective" NAT (e.g., MAPT-AS1) is downregulated under pathogenic conditions. As a relatively underexplored endogenous control mechanism of protein expression, NATs may present novel mechanistic targets to prevent or ameliorate aging-related disorders.

Micro-RNA profiles of pathology and resilience in posterior cingulate cortex of cognitively intact elders.

The posterior cingulate cortex (PCC) is a key hub of the default mode network underlying autobiographical memory retrieval, which falters early in the progression of Alzheimer's disease (AD). We recently performed RNA sequencing of post-mortem PCC tissue samples from 26 elderly Rush Religious Orders Study participants who came to autopsy with an ante-mortem diagnosis of no cognitive impairment but who collectively displayed a range of Braak I-IV neurofibrillary tangle stages. Notably, cognitively unimpaired subjects displaying high Braak stages may represent cognitive resilience to AD pathology. Transcriptomic data revealed elevated synaptic and ATP-related gene expression in Braak Stages III/IV compared with Stages I/II, suggesting these pathways may be related to PCC resilience. We also mined expression profiles for small non-coding micro-RNAs (miRNAs), which regulate mRNA stability and may represent an underexplored potential mechanism of resilience through the fine-tuning of gene expression within complex cellular networks. Twelve miRNAs were identified as differentially expressed between Braak Stages I/II and III/IV. However, the extent to which the levels of all identified miRNAs were associated with subject demographics, neuropsychological test performance and/or neuropathological diagnostic criteria within this cohort was not explored. Here, we report that a total of 667 miRNAs are significantly associated (rho > 0.38, P < 0.05) with subject variables. There were significant positive correlations between miRNA expression levels and age, perceptual orientation and perceptual speed. By contrast, higher miRNA levels correlated negatively with semantic and episodic memory. Higher expression of 15 miRNAs associated with lower Braak Stages I-II and 47 miRNAs were associated with higher Braak Stages III-IV, suggesting additional mechanistic influences of PCC miRNA expression with resilience. Pathway analysis showed enrichment for miRNAs operating in pathways related to lysine degradation and fatty acid synthesis and metabolism. Finally, we demonstrated that the 12 resilience-related miRNAs differentially expressed in Braak Stages I/II versus Braak Stages III/IV were predicted to regulate mRNAs related to amyloid processing, tau and inflammation. In summary, we demonstrate a dynamic state wherein differential PCC miRNA levels are associated with cognitive performance and post-mortem neuropathological AD diagnostic criteria in cognitively intact elders. We posit these relationships may inform miRNA transcriptional alterations within the PCC relevant to potential early protective (resilience) or pathogenic (pre-clinical or prodromal) responses to disease pathogenesis and thus may be therapeutic targets.

Transcriptomic profiling of early synucleinopathy in rats induced with preformed fibrils.

Examination of early phases of synucleinopathy when inclusions are present, but long before neurodegeneration occurs, is critical to both understanding disease progression and the development of disease modifying therapies. The rat alpha-synuclein (α-syn) preformed fibril (PFF) model induces synchronized synucleinopathy that recapitulates the pathological features of Parkinson's disease (PD) and can be used to study synucleinopathy progression. In this model, phosphorylated α-syn (pSyn) inclusion-containing neurons and reactive microglia (major histocompatibility complex-II immunoreactive) peak in the substantia nigra pars compacta (SNpc) months before appreciable neurodegeneration. However, it remains unclear which specific genes are driving these phenotypic changes. To identify transcriptional changes associated with early synucleinopathy, we used laser capture microdissection of the SNpc paired with RNA sequencing (RNASeq). Precision collection of the SNpc allowed for the assessment of differential transcript expression in the nigral dopamine neurons and proximal glia. Transcripts upregulated in early synucleinopathy were mainly associated with an immune response, whereas transcripts downregulated were associated with neurotransmission and the dopamine pathway. A subset of 29 transcripts associated with neurotransmission/vesicular release and the dopamine pathway were verified in a separate cohort of males and females to confirm reproducibility. Within this subset, fluorescent in situ hybridization (FISH) was used to localize decreases in the Syt1 and Slc6a3 transcripts to pSyn inclusion-containing neurons. Identification of transcriptional changes in early synucleinopathy provides insight into the molecular mechanisms driving neurodegeneration.

Complement activation fragment C5a receptors, CD88 and C5L2, are associated with neurofibrillary pathology.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative dementia characterized by the decline of cognition and the presence of neuropathological changes including neuronal loss, neurofibrillary pathology and extracellular senile plaques. A neuroinflammatory process is also triggered and complement activation has been hypothesized to have a relevant role in this local inflammatory response. C5a, a proinflammatory anaphylatoxin generated after complement activation, exerts its chemotactic and inflammatory functions through the CD88 receptor while the more recently discovered C5L2 receptor has been postulated to have an anti-inflammatory role. Previously, we reported that a CD88 specific antagonist (PMX205) decreased the pathology and improved cognition in transgenic models of AD suggesting that C5a/C5aR interaction has an important role in the progression of the disease. METHODS: The present study characterizes the expression of the two receptors for C5a in human brain with confirmed post mortem diagnosis of vascular dementia (VD) or AD as well as age matched controls by immunohistochemistry and Western blot analysis using several antibodies against different epitopes of the human receptors. RESULTS: The CD88 and C5L2 antibodies revealed increased expression of both receptors in AD samples as compared to age-matched controls or VD brain tissue by Western blot and immunohistochemistry, using multiple antibodies and distinct cohorts of brain tissue. Immunostaining showed that both the C5L2 and CD88 antibodies similarly labeled abundant neurofibrillary tangles, neuropil threads and dystrophic neurites associated with plaques in the hippocampus and frontal cortex of AD cases. In contrast, little or no neuronal staining, tangles or dystrophic neurites associated with plaques were observed in control or VD brains. CD88 and C5L2 receptors are associated with both early (AT8) and mature (PHF1) neurofibrillary tangles and can be found either independently or colocalized with each other. CONCLUSIONS: The observed association of CD88 and C5L2 with neurofibrillary pathology suggests a common altered pathway of degradation.

Rac1b increases with progressive tau pathology within cholinergic nucleus basalis neurons in Alzheimer's disease.

Cholinergic basal forebrain (CBF) nucleus basalis (NB) neurons display neurofibrillary tangles (NFTs) during Alzheimer's disease (AD) progression, yet the mechanisms underlying this selective vulnerability are currently unclear. Rac1, a member of the Rho family of GTPases, may interact with the proapoptotic pan-neurotrophin receptor p75(NTR) to induce neuronal cytoskeletal abnormalities in AD NB neurons. Herein, we examined the expression of Rac1b, a constitutively active splice variant of Rac1, in NB cholinergic neurons during AD progression. CBF tissues harvested from people who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment, or AD were immunolabeled for both p75(NTR) and Rac1b. Rac1b appeared as cytoplasmic diffuse granules, loosely aggregated filaments, or compact spheres in p75(NTR)-positive NB neurons. Although Rac1b colocalized with tau cytoskeletal markers, the percentage of p75(NTR)-immunoreactive neurons expressing Rac1b was significantly increased only in AD compared with both mild cognitive impairment and NCI. Furthermore, single-cell gene expression profiling with custom-designed microarrays showed down-regulation of caveolin 2, GNB4, and lipase A in AD Rac1b-positive/p75(NTR)-labeled NB neurons compared with Rac1b-negative/p75(NTR)-positive perikarya in NCI. These proteins are involved in Rac1 pathway/cell cycle progression and lipid metabolism. These data suggest that Rac1b expression acts as a modulator or transducer of various signaling pathways that lead to NFT formation and membrane dysfunction in a subgroup of CBF NB neurons in AD.

Vascular and Nonvascular Mechanisms of Cognitive Impairment and Dementia.

Aging, familial gene mutations, and genetic, environmental, and modifiable lifestyle risk factors predispose individuals to cognitive impairment or dementia by influencing the efficacy of multiple, often interdependent cellular and molecular homeostatic pathways mediating neuronal, glial, and vascular integrity and, ultimately, cognitive status. This review summarizes data from foundational and recent breakthrough studies to highlight common and differential vascular and nonvascular pathogenic mechanisms underlying the progression of Alzheimer disease, vascular dementia, frontotemporal dementia, and dementia with Lewy bodies.

Application of robust regression in translational neuroscience studies with non-Gaussian outcome data.

Linear regression is one of the most used statistical techniques in neuroscience, including the study of the neuropathology of Alzheimer's disease (AD) dementia. However, the practical utility of this approach is often limited because dependent variables are often highly skewed and fail to meet the assumption of normality. Applying linear regression analyses to highly skewed datasets can generate imprecise results, which lead to erroneous estimates derived from statistical models. Furthermore, the presence of outliers can introduce unwanted bias, which affect estimates derived from linear regression models. Although a variety of data transformations can be utilized to mitigate these problems, these approaches are also associated with various caveats. By contrast, a robust regression approach does not impose distributional assumptions on data allowing for results to be interpreted in a similar manner to that derived using a linear regression analysis. Here, we demonstrate the utility of applying robust regression to the analysis of data derived from studies of human brain neurodegeneration where the error distribution of a dependent variable does not meet the assumption of normality. We show that the application of a robust regression approach to two independent published human clinical neuropathologic data sets provides reliable estimates of associations. We also demonstrate that results from a linear regression analysis can be biased if the dependent variable is significantly skewed, further indicating robust regression as a suitable alternate approach.