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1.
Mol Neurodegener ; 18(1): 2, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36609403

RESUMO

BACKGROUND: Alzheimer's disease (AD) is neuropathologically characterized by amyloid-beta (Aß) plaques and neurofibrillary tangles. The main protein components of these hallmarks include Aß40, Aß42, tau, phosphor-tau, and APOE. We hypothesize that genetic variants influence the levels and solubility of these AD-related proteins in the brain; identifying these may provide key insights into disease pathogenesis. METHODS: Genome-wide genotypes were collected from 441 AD cases, imputed to the haplotype reference consortium (HRC) panel, and filtered for quality and frequency. Temporal cortex levels of five AD-related proteins from three fractions, buffer-soluble (TBS), detergent-soluble (Triton-X = TX), and insoluble (Formic acid = FA), were available for these same individuals. Variants were tested for association with each quantitative biochemical measure using linear regression, and GSA-SNP2 was used to identify enriched Gene Ontology (GO) terms. Implicated variants and genes were further assessed for association with other relevant variables. RESULTS: We identified genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD-related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. CONCLUSIONS: Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/metabolismo , Estudo de Associação Genômica Ampla , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Placa Amiloide/patologia , Fenótipo , Apolipoproteínas E/metabolismo , Proteínas tau/metabolismo
2.
J Alzheimers Dis ; 91(2): 683-695, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36502330

RESUMO

BACKGROUND: The strongest risk factor for the development of Alzheimer's disease (AD) is age. The progression of Braak stage and Thal phase with age has been demonstrated. However, prior studies did not include cognitive status. OBJECTIVE: We set out to define normative values for Alzheimer-type pathologic changes in individuals without cognitive decline, and then define levels that would qualify them to be resistant to or resilient against these changes. METHODS: Utilizing neuropathology data obtained from the National Alzheimer's Coordinating Center (NACC), we demonstrate the age-related progression of Alzheimer-type pathologic changes in cognitively normal individuals (CDR = 0, n = 542). With plots generated from these data, we establish standard lines that may be utilized to measure the extent to which an individual's Alzheimer-type pathology varies from the estimated normal range of pathology. RESULTS: Although Braak stage and Thal phase progressively increase with age in cognitively normal individuals, the Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque score and Alzheimer's disease neuropathologic change remain at low levels. CONCLUSION: These findings suggest that an increasing burden of neuritic plaques is a strong predictor of cognitive decline, whereas, neurofibrillary degeneration and amyloid-ß (diffuse) plaque deposition, both to some degree, are normal pathologic changes of aging that occur in almost all individuals regardless of cognitive status. Furthermore, we have defined the amount of neuropathologic change in cognitively normal individuals that would qualify them to be "resilient" against the pathology (significantly above the normative values for age, but still cognitively normal) or "resistant" to the development of pathology (significantly below the normative values for age).


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Emaranhados Neurofibrilares/patologia , Peptídeos beta-Amiloides , Envelhecimento/patologia , Placa Amiloide/patologia
3.
Acta Neuropathol Commun ; 10(1): 182, 2022 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-36529803

RESUMO

The long-lived Chilean rodent (Octodon degus) has been reported to show spontaneous age-dependent neuropathology and cognitive impairments similar to those observed in human AD. However, the handful of published papers on degus of differing genetic backgrounds yield inconsistent findings about sporadic AD-like pathological features, with notably differing results between lab in-bred degus versus outbred degus. This motivates more extensive characterization of spontaneously occurring AD-like pathology and behavior in degus. In the present study, we show AD-like neuropathological markers in the form of amyloid deposits and tau abnormalities in a cognitively impaired subset of aged outbred degus. Compared to the aged degus that show normal burrowing behavior, the age-matched degus with burrowing behavior deficits correlatively exhibit detectable human AD-like Aß deposits and tau neuropathology, along with neuroinflammatory markers that include enhanced microglial activation and higher numbers of reactive astrocytes in the brain. This subset of cognitively impaired aged degus also exhibits cerebral amyloid angiopathy and tauopathy. We find robust neurodegenerative features in behaviorally deficient aged degus, including hippocampal neuronal loss, altered parvalbumin and perineuronal net staining in the cortex, and increased c-Fos neuronal activation in the cortex that is consistent with the neural circuit hyperactivity reported in human AD patients. By focusing on the subset of aged degus that show AD-like behavioral deficits and correlative neuropathology, our findings establish outbred degus as a natural model of sporadic AD and demonstrate the potential importance of wild-type outbred genetic backgrounds for AD pathogenesis.


Assuntos
Doença de Alzheimer , Octodon , Animais , Humanos , Idoso , Doença de Alzheimer/patologia , Modelos Animais de Doenças , Placa Amiloide/patologia , Encéfalo/patologia
4.
Adv Exp Med Biol ; 1395: 335-340, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36527658

RESUMO

Alzheimer's disease (AD) is a consequence of complex interactions of age-related neurodegeneration and vascular-associated pathologies, affecting more than 44 million people worldwide. For the last decade, it has been suggested that chronic brain hypoperfusion and consequent hypoxia play a direct role in the pathogenesis of AD. However, current treatments of AD have not focused on restoring or improving microvascular perfusion. In a previous study, we showed that drag reducing polymers (DRP) enhance cerebral blood flow and tissue oxygenation. We hypothesised that haemorheologic enhancement of cerebral perfusion by DRP would be useful for treating Alzheimer's disease. We used double transgenic B6C3-Tg(APPswe, PSEN1dE9) 85Dbo/Mmjax AD mice. DRP or vehicle (saline) was i.v. injected every week starting at four months of age till 12 months of age (10 mice/group). In-vivo 2-photon laser scanning microscopy was used to evaluate amyloid plaques development, cerebral microcirculation, and tissue oxygen supply/metabolic status (NADH autofluorescence). The imaging sessions were repeated once a month till 12 months of age. Statistical analyses were done by independent Student's t-test or Kolmogorov-Smirnov tests where appropriate. Differences between groups and time were determined using a two-way repeated measures ANOVA analysis for multiple comparisons and post hoc testing using the Mann-Whitney U test. In the vehicle group, numerous plaques completely formed in the cortex by nine months of age. The development of plaques accumulation was accompanied by cerebral microcirculation disturbances, reduction in tissue oxygen supply and metabolic impairment (NADH increase). DRP mitigated microcirculation and tissue oxygen supply reduction - microvascular perfusion was 29.5 ± 5%, and tissue oxygen supply was 22 ± 4% higher than in the vehicle group (p < 0.05). In the DRP group, amyloid plaques deposition was substantially less than in the vehicle group (p < 0.05). Thus, rheological enhancement of blood flow by DRP is associated with reduced rate of beta amyloid plaques deposition in AD mice.


Assuntos
Doença de Alzheimer , Placa Amiloide , Polímeros , Animais , Camundongos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Circulação Cerebrovascular , Modelos Animais de Doenças , Hipóxia/patologia , Camundongos Transgênicos , NAD/metabolismo , Oxigênio , Perfusão , Placa Amiloide/patologia , Polímeros/metabolismo , Polímeros/farmacologia
5.
Int J Mol Sci ; 23(23)2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36499362

RESUMO

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, characterised by the accumulation of senile plaques and tau tangles, neurodegeneration, and neuroinflammation in the brain. The development of AD is a pathological cascade starting according to the amyloid hypothesis with the accumulation and aggregation of the ß-amyloid peptide (Aß), which induces hyperphosphorylation of tau and promotes the pro-inflammatory activation of microglia leading to synaptic loss and, ultimately, neuronal death. Modelling AD-related processes is important for both studying the molecular basis of the disease and the development of novel therapeutics. The replication of these processes is often achieved with the use of a purified Aß peptide. However, Aß preparations obtained from different sources can have strikingly different properties. This review aims to compare the structure and biological effects of Aß oligomers and aggregates of a higher order: synthetic, recombinant, purified from cell culture, or extracted from brain tissue. The authors summarise the applicability of Aß preparations for modelling Aß aggregation, neurotoxicity, cytoskeleton damage, receptor toxicity in vitro and cerebral amyloidosis, synaptic plasticity disruption, and cognitive impairment in vivo and ex vivo. Further, the paper discusses the causes of the reported differences in the effect of Aß obtained from the sources mentioned above. This review points to the importance of the source of Aß for AD modelling and could help researchers to choose the optimal way to model the Aß-induced abnormalities.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Humanos , Idoso , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Placa Amiloide/patologia , Encéfalo/metabolismo , Desenvolvimento de Medicamentos
6.
Mol Neurodegener ; 17(1): 72, 2022 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-36348357

RESUMO

Alzheimer's disease (AD) is the most common cause of dementia worldwide, and its prevalence is rapidly increasing due to extended lifespans. Among the increasing number of genetic risk factors identified, the apolipoprotein E (APOE) gene remains the strongest and most prevalent, impacting more than half of all AD cases. While the ε4 allele of the APOE gene significantly increases AD risk, the ε2 allele is protective relative to the common ε3 allele. These gene alleles encode three apoE protein isoforms that differ at two amino acid positions. The primary physiological function of apoE is to mediate lipid transport in the brain and periphery; however, additional functions of apoE in diverse biological functions have been recognized. Pathogenically, apoE seeds amyloid-ß (Aß) plaques in the brain with apoE4 driving earlier and more abundant amyloids. ApoE isoforms also have differential effects on multiple Aß-related or Aß-independent pathways. The complexity of apoE biology and pathobiology presents challenges to designing effective apoE-targeted therapeutic strategies. This review examines the key pathobiological pathways of apoE and related targeting strategies with a specific focus on the latest technological advances and tools.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Doença de Alzheimer/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Apolipoproteína E4/genética , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide/patologia , Alelos
7.
Fluids Barriers CNS ; 19(1): 88, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36345028

RESUMO

BACKGROUND: While aging is the main risk factor for Alzheimer´s disease (AD), emerging evidence suggests that metabolic alterations such as type 2 diabetes (T2D) are also major contributors. Indeed, several studies have described a close relationship between AD and T2D with clinical evidence showing that both diseases coexist. A hallmark pathological event in AD is amyloid-ß (Aß) deposition in the brain as either amyloid plaques or around leptomeningeal and cortical arterioles, thus constituting cerebral amyloid angiopathy (CAA). CAA is observed in 85-95% of autopsy cases with AD and it contributes to AD pathology by limiting perivascular drainage of Aß. METHODS: To further explore these alterations when AD and T2D coexist, we have used in vivo multiphoton microscopy to analyze over time the Aß deposition in the form of plaques and CAA in a relevant model of AD (APPswe/PS1dE9) combined with T2D (db/db). We have simultaneously assessed the effects of high-fat diet-induced prediabetes in AD mice. Since both plaques and CAA are implicated in oxidative-stress mediated vascular damage in the brain, as well as in the activation of matrix metalloproteinases (MMP), we have also analyzed oxidative stress by Amplex Red oxidation, MMP activity by DQ™ Gelatin, and vascular functionality. RESULTS: We found that prediabetes accelerates amyloid plaque and CAA deposition, suggesting that initial metabolic alterations may directly affect AD pathology. T2D significantly affects vascular pathology and CAA deposition, which is increased in AD-T2D mice, suggesting that T2D favors vascular accumulation of Aß. Moreover, T2D synergistically contributes to increase CAA mediated oxidative stress and MMP activation, affecting red blood cell velocity. CONCLUSIONS: Our data support the cross-talk between metabolic disease and Aß deposition that affects vascular integrity, ultimately contributing to AD pathology and related functional changes in the brain microvasculature.


Assuntos
Doença de Alzheimer , Angiopatia Amiloide Cerebral , Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Animais , Camundongos , Doença de Alzheimer/metabolismo , Modelos Animais de Doenças , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Estado Pré-Diabético/complicações , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/patologia , Angiopatia Amiloide Cerebral/metabolismo , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide/complicações , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Encéfalo/metabolismo , Metaloproteinases da Matriz
8.
Acta Neuropathol Commun ; 10(1): 157, 2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36316708

RESUMO

Tauopathies are a category of neurodegenerative diseases characterized by the presence of abnormal tau protein-containing neurofibrillary tangles (NFTs). NFTs are universally observed in aging, occurring with or without the concomitant accumulation of amyloid-beta peptide (Aß) in plaques that typifies Alzheimer disease (AD), the most common tauopathy. Primary age-related tauopathy (PART) is an Aß-independent process that affects the medial temporal lobe in both cognitively normal and impaired subjects. Determinants of symptomology in subjects with PART are poorly understood and require clinicopathologic correlation; however, classical approaches to staging tau pathology have limited quantitative reproducibility. As such, there is a critical need for unbiased methods to quantitatively analyze tau pathology on the histological level. Artificial intelligence (AI)-based convolutional neural networks (CNNs) generate highly accurate and precise computer vision assessments of digitized pathology slides, yielding novel histology metrics at scale. Here, we performed a retrospective autopsy study of a large cohort (n = 706) of human post-mortem brain tissues from normal and cognitively impaired elderly individuals with mild or no Aß plaques (average age of death of 83.1 yr, range 55-110). We utilized a CNN trained to segment NFTs on hippocampus sections immunohistochemically stained with antisera recognizing abnormal hyperphosphorylated tau (p-tau), which yielded metrics of regional NFT counts, NFT positive pixel density, as well as a novel graph-theory based metric measuring the spatial distribution of NFTs. We found that several AI-derived NFT metrics significantly predicted the presence of cognitive impairment in both the hippocampus proper and entorhinal cortex (p < 0.0001). When controlling for age, AI-derived NFT counts still significantly predicted the presence of cognitive impairment (p = 0.04 in the entorhinal cortex; p = 0.04 overall). In contrast, Braak stage did not predict cognitive impairment in either age-adjusted or unadjusted models. These findings support the hypothesis that NFT burden correlates with cognitive impairment in PART. Furthermore, our analysis strongly suggests that AI-derived metrics of tau pathology provide a powerful tool that can deepen our understanding of the role of neurofibrillary degeneration in cognitive impairment.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Tauopatias , Humanos , Idoso , Emaranhados Neurofibrilares/patologia , Inteligência Artificial , Estudos Retrospectivos , Reprodutibilidade dos Testes , Proteínas tau/análise , Tauopatias/patologia , Doença de Alzheimer/patologia , Placa Amiloide/patologia , Disfunção Cognitiva/patologia
9.
Curr Neurol Neurosci Rep ; 22(11): 709-719, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36269539

RESUMO

PURPOSE OF REVIEW: Amyloid beta (Aß) plaque accumulation is a hallmark pathology contributing to Alzheimer's disease (AD) and is widely hypothesized to lead to cognitive decline. Decades of research into anti-Aß immunotherapies provide evidence for increased Aß clearance from the brain; however, this is frequently accompanied by complicated vascular deficits. This article reviews the history of anti-Aß immunotherapies and clinical findings and provides recommendations moving forward. RECENT FINDINGS: In 20 years of both animal and human studies, anti-Aß immunotherapies have been a prevalent avenue of reducing hallmark Aß plaques. In both models and with different anti-Aß antibody designs, amyloid-related imaging abnormalities (ARIA) indicating severe cerebrovascular compromise have been common and concerning occurrence. ARIA caused by anti-Aß immunotherapy has been noted since the early 2000s, and the mechanisms driving it are still unknown. Recent approval of aducanumab comes with renewed urgency to consider vascular deficits caused by anti-Aß immunotherapy.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Animais , Humanos , Placa Amiloide/tratamento farmacológico , Placa Amiloide/patologia , Doença de Alzheimer/tratamento farmacológico , Proteínas Amiloidogênicas , Amiloide , Imunoterapia/métodos , Fatores Imunológicos , Modelos Animais de Doenças
10.
PLoS One ; 17(10): e0276107, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36256604

RESUMO

The blood-brain barrier (BBB) presents a major obstacle in developing specific diagnostic imaging agents for many neurological disorders. In this study we aimed to generate single domain anti-mouse transferrin receptor antibodies (anti-mTfR VHHs) to mediate BBB transcytosis as components of novel MRI molecular contrast imaging agents. Anti-mTfR VHHs were produced by immunizing a llama with mTfR, generation of a VHH phage display library, immunopanning, and in vitro characterization of candidates. Site directed mutagenesis was used to generate additional variants. VHH fusions with neurotensin (NT) allowed rapid, hypothermia-based screening for VHH-mediated BBB transcytosis in wild-type mice. One anti-mTfR VHH variant was fused with an anti-amyloid-beta (Aß) VHH dimer and labeled with fluorescent dye for direct assessment of in vivo target engagement in a mouse model of AD-related Aß plaque pathology. An anti-mTfR VHH called M1 and variants had binding affinities to mTfR of <1nM to 1.52nM. The affinity of the VHH binding to mTfR correlated with the efficiency of the VHH-NT induced hypothermia effects after intravenous injection of 600 nmol/kg body weight, ranging from undetectable for nonbinding mutants to -6°C for the best mutants. The anti-mTfR VHH variant M1P96H with the strongest hypothermia effect was fused to the anti-Aß VHH dimer and labeled with Alexa647; the dye-labeled VHH fusion construct still bound both mTfR and Aß plaques at concentrations as low as 0.22 nM. However, after intravenous injection at 600 nmol/kg body weight into APP/PS1 transgenic mice, there was no detectible labeling of plaques above control levels. Thus, NT-induced hypothermia did not correlate with direct target engagement in cortex, likely because the concentration required for NT-induced hypothermia was lower than the concentration required to produce in situ labeling. These findings reveal an important dissociation between NT-induced hypothermia, presumably mediated by hypothalamus, and direct engagement with Aß-plaques in cortex. Additional methods to assess anti-mTfR VHH BBB transcytosis will need to be developed for anti-mTfR VHH screening and the development of novel MRI molecular contrast agents.


Assuntos
Doença de Alzheimer , Camelídeos Americanos , Hipotermia , Animais , Camundongos , Barreira Hematoencefálica/metabolismo , Neurotensina/metabolismo , Doença de Alzheimer/metabolismo , Meios de Contraste/metabolismo , Hipotermia/metabolismo , Corantes Fluorescentes/metabolismo , Encéfalo/metabolismo , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide/patologia , Camundongos Transgênicos , Modelos Animais de Doenças , Transcitose , Peso Corporal
11.
J Vet Med Sci ; 84(12): 1563-1573, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36288928

RESUMO

Cerebral amyloid ß (Aß) deposition is a pathological hallmark of Alzheimer's disease (AD). There are several molecular species of Aß, including Aß40, Aß42, and Aß43, and the pathological roles of Aß43 have attracted particular attention in recent years. Aß43 is mainly deposited as senile plaques (SPs) in AD brains, and is known to be more amyloidogenic and neurotoxic than Aß42 and Aß40. Aß40 and Aß42 deposition have been demonstrated in several animal species, while Aß43 deposition has not been studied in animals. The brains of sea lions, dogs, and cats exhibit unique age-related Aß pathologies. In the present study, the deposition patterns of Aß40, Aß42, and Aß43 were examined immunohistochemically in the brains of aged dogs (n=52), sea lions (n=5), and cats (n=17). In dogs, most cerebral amyloid angiopathy (CAA) lesions and primitive SPs were positive for Aß42, Aß43, and Aß40. However, diffuse SPs and capillary CAA lesions were negative for Aß40. In sea lions, all SPs and most CAA lesions were positive for Aß42, Aß43, and Aß40, while capillary CAA lesions were negative for Aß40. In cats, Aß42-immunopositive granular aggregates and arteriole and capillary CAA lesions were positive for Aß43, but negative for Aß40. Double-labelling immunohistochemistry revealed the co-localization of Aß42 and Aß43. These findings suggest that Aß43 and Aß42 are frequently deposited in the brains of Carnivora animals and may play an important role in Aß pathology.


Assuntos
Doença de Alzheimer , Doenças do Gato , Angiopatia Amiloide Cerebral , Doenças do Cão , Leões-Marinhos , Animais , Gatos , Cães , Peptídeos beta-Amiloides/metabolismo , Fragmentos de Peptídeos , Placa Amiloide/veterinária , Placa Amiloide/patologia , Angiopatia Amiloide Cerebral/veterinária , Angiopatia Amiloide Cerebral/patologia , Doença de Alzheimer/patologia , Doença de Alzheimer/veterinária , Encéfalo/patologia
12.
Biomolecules ; 12(10)2022 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-36291553

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly. The two cardinal neuropathological hallmarks of AD are the senile plaques, which are extracellular deposits mainly constituted by beta-amyloids, and neurofibrillary tangles formed by abnormally phosphorylated Tau (p-Tau) located in the cytoplasm of neurons. Although the research has made relevant progress in the management of the disease, the treatment is still lacking. Only symptomatic medications exist for the disease, and, in the meantime, laboratories worldwide are investigating disease-modifying treatments for AD. In the present review, results centered on the use of peptides of different sizes involved in AD are presented.


Assuntos
Doença de Alzheimer , Humanos , Idoso , Doença de Alzheimer/metabolismo , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Neurônios/metabolismo , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia
13.
Int J Mol Sci ; 23(20)2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36293147

RESUMO

The typical pathological features of Alzheimer's disease (AD) are the accumulation of amyloid plaques in the brain and reactivity of glial cells such as astrocytes and microglia. Clinically, the development of AD and obesity are known to be correlated. In this study, we analyzed the changes in AD pathological characteristics in 5XFAD mice after obesity induction through a high-fat diet (HFD). Surprisingly, high-density lipoprotein and apolipoprotein AI (APOA-I) serum levels were increased without low-density lipoprotein alteration in both HFD groups. The reactivity of astrocytes and microglia in the dentate gyrus of the hippocampus and fornix of the hypothalamus in 5XFAD mice was decreased in the transgenic (TG)-HFD high group. Finally, the accumulation of amyloid plaques in the dentate gyrus region of the hippocampus was also significantly decreased in the TG-HFD high group. These results suggest that increased high-density lipoprotein level, especially with increased APOA-I serum level, alleviates the pathological features of AD and could be a new potential therapeutic strategy for AD treatment.


Assuntos
Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/patologia , Placa Amiloide/patologia , Dieta Hiperlipídica/efeitos adversos , Peptídeos beta-Amiloides , Apolipoproteína A-I , Lipoproteínas HDL/uso terapêutico , Camundongos Transgênicos , Modelos Animais de Doenças , Obesidade/etiologia , Lipoproteínas LDL
14.
Acta Neuropathol Commun ; 10(1): 153, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36307888

RESUMO

Protein misfolding is a prominent pathological hallmark of neurodegenerative disorders, including Alzheimer's disease (AD). Studies have shown that the diversity of ß sheet-rich protein deposits (such as amyloid ß plaques and neurofibrillary tangles), present across different brain regions, might underlie different disease phenotypes and only certain types of aggregates might be associated with cognitive decline. Conformationally sensitive fluorescent amyloid probes have the ability to report different structures of protein aggregates by virtue of their shifting emission spectra. Here we defined the binding affinity of the fluorescent amyloid probes BSB and MCAAD to disease-relevant protein aggregates, and combined the two probes to examine formalin-fixed paraffin-embedded mouse and human brain samples. Coupled with quantitative spectral phasor analysis, the dual-probe staining approach revealed remarkable heterogeneity of protein aggregates across the samples. Distinct emission spectra were consistent with certain types of deposits present in the mouse and human brain sections. The sensitivity of this staining, imaging and analysis approach outperformed conventional immunohistochemistry with the detected spectral differences between the greater parenchyma of cognitively normal and AD cases indicating a subtle yet widespread proteopathy associated with disease. Our method offers more sensitive, objective, and quantitative examination of protein misfolding pathology using conventional tissue sections.


Assuntos
Doença de Alzheimer , Amiloidose , Animais , Humanos , Camundongos , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/patologia , Proteínas tau/metabolismo , Agregados Proteicos , Espectrometria de Fluorescência , Placa Amiloide/patologia , Amiloide/metabolismo , Encéfalo/patologia , Amiloidose/patologia , Corantes Fluorescentes/metabolismo
15.
Sci Rep ; 12(1): 16488, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36182964

RESUMO

Blood-brain barrier (BBB) dysfunction is emerging as a key pathogenic factor in the progression of Alzheimer's disease (AD), where increased microvascular endothelial permeability has been proposed to play an important role. However, the molecular mechanisms leading to increased brain microvascular permeability in AD are not fully understood. We studied brain endothelial permeability in female APPswe/PS1∆E9 (APP/PS1) mice which constitute a transgenic mouse model of amyloid-beta (Aß) amyloidosis and found that permeability increases with aging in the areas showing the greatest amyloid plaque deposition. We performed an unbiased bulk RNA-sequencing analysis of brain endothelial cells (BECs) in female APP/PS1 transgenic mice. We observed that upregulation of interferon signaling gene expression pathways in BECs was among the most prominent transcriptomic signatures in the brain endothelium. Immunofluorescence analysis of isolated BECs from female APP/PS1 mice demonstrated higher levels of the Type I interferon-stimulated gene IFIT2. Immunoblotting of APP/PS1 BECs showed downregulation of the adherens junction protein VE-cadherin. Stimulation of human brain endothelial cells with interferon-ß decreased the levels of the adherens junction protein VE-cadherin as well as tight junction proteins Occludin and Claudin-5 and increased barrier leakiness. Depletion of the Type I interferon receptor in human brain endothelial cells prevented interferon-ß-induced VE-cadherin downregulation and restored endothelial barrier integrity. Our study suggests that Type I interferon signaling contributes to brain endothelial dysfunction in AD.


Assuntos
Doença de Alzheimer , Interferon Tipo I , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Claudina-5/metabolismo , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Endotélio/metabolismo , Feminino , Humanos , Interferon Tipo I/metabolismo , Interferon beta/metabolismo , Camundongos , Camundongos Transgênicos , Ocludina/metabolismo , Placa Amiloide/patologia , RNA/metabolismo , Receptor de Interferon alfa e beta/metabolismo , Proteínas de Junções Íntimas/metabolismo
16.
Proc Natl Acad Sci U S A ; 119(41): e2204306119, 2022 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-36191221

RESUMO

Recurrent seizure is a common comorbidity in early-stage Alzheimer's disease (AD) and may contribute to AD pathogenesis and cognitive decline. Similarly, many mouse models of Alzheimer's disease that overproduce amyloid beta are prone to epileptiform seizures that may result in early sudden death. We studied one such model, designated APP/PS1, and found that mutation of the TAM receptor tyrosine kinase (RTK) Mer or its ligand Gas6 greatly exacerbated early death. Lethality was tied to violent seizures that appeared to initiate in the dentate gyrus (DG) of the hippocampus, where Mer plays an essential role in the microglial phagocytosis of both apoptotic and newborn cells normally generated during adult neurogenesis. We found that newborn DG neurons and excitatory synapses between the DG and the cornu ammonis field 3 (CA3) field of the hippocampus were increased in TAM-deficient mice, and that premature death and adult neurogenesis in these mice were coincident. In contrast, the incidence of lethal seizures and the deposition of dense-core amyloid plaques were strongly anticorrelated. Together, these results argue that TAM-mediated phagocytosis sculpts synaptic connectivity in the hippocampus, and that seizure-inducing amyloid beta polymers are present prior to the formation of dense-core plaques.


Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Convulsões , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animais , Giro Denteado , Modelos Animais de Doenças , Hipocampo/metabolismo , Ligantes , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Neurogênese , Fagocitose , Placa Amiloide/patologia , Polímeros , Proteínas Tirosina Quinases , Convulsões/genética , Convulsões/patologia
17.
Neurobiol Dis ; 174: 105880, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36191742

RESUMO

The classic pathologic hallmarks of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles (AD neuropathologic changes, or ADNC). However, brains from individuals clinically diagnosed with "AD-type" (amnestic) dementia usually harbor heterogeneous neuropathologies in addition to, or other than, ADNC. We hypothesized that some AD-type dementia associated genetic single nucleotide variants (SNVs) identified from large genomewide association studies (GWAS) were associated with non-ADNC neuropathologies. To test this hypothesis, we analyzed data from multiple studies with available genotype and neuropathologic phenotype information. Clinical AD/dementia risk alleles of interest were derived from the very large GWAS by Bellenguez et al. (2022) who reported 83 clinical AD/dementia-linked SNVs in addition to the APOE risk alleles. To query the pathologic phenotypes associated with variation of those SNVs, National Alzheimer's disease Coordinating Center (NACC) neuropathologic data were linked to AD Sequencing Project (ADSP) and AD Genomics Consortium (ADGC) data. Separate data were obtained from the harmonized Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). A total of 4811 European participants had at least ADNC neuropathology data and also genotype data available; data were meta-analyzed across cohorts. As expected, a subset of dementia-associated SNVs were associated with ADNC risk in Europeans-e.g., BIN1, PICALM, CR1, MME, and COX7C. Other gene variants linked to (clinical) AD dementia were associated with non-ADNC pathologies. For example, the associations of GRN and TMEM106B SNVs with limbic-predominant age-related TDP-43 neuropathologic changes (LATE-NC) were replicated. In addition, SNVs in TNIP1 and WNT3 previously reported as AD-related were instead associated with hippocampal sclerosis pathology. Some genotype/neuropathology association trends were not statistically significant at P < 0.05 after correcting for multiple testing, but were intriguing. For example, variants in SORL1 and TPCN1 showed trends for association with LATE-NC whereas Lewy body pathology trended toward association with USP6NL and BIN1 gene variants. A smaller cohort of non-European subjects (n = 273, approximately one-half of whom were African-Americans) provided the basis for additional exploratory analyses. Overall, these findings were consistent with the hypothesis that some genetic variants linked to AD dementia risk exert their affect by influencing non-ADNC neuropathologies.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Estudo de Associação Genômica Ampla , Emaranhados Neurofibrilares/genética , Emaranhados Neurofibrilares/patologia , Placa Amiloide/genética , Placa Amiloide/patologia , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética
18.
J Alzheimers Dis ; 90(1): 405-417, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36213996

RESUMO

BACKGROUND: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes. OBJECTIVE: Investigate the contributions of vascular factors and cancer to dementia and neuropathology. METHODS: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology. RESULTS: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95-106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19-0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39-163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17-0.78]; p < 0.01) and lower Braak stage (p = 0.01). CONCLUSION: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-ß plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old.


Assuntos
Doença de Alzheimer , Transtornos Cerebrovasculares , Doença da Artéria Coronariana , Diabetes Mellitus , Neoplasias , Doenças do Sistema Nervoso , Feminino , Humanos , Idoso de 80 Anos ou mais , Masculino , Doença de Alzheimer/patologia , Neuropatologia , Placa Amiloide/patologia , Transtornos Cerebrovasculares/epidemiologia , Transtornos Cerebrovasculares/patologia , Apolipoproteínas E , Diabetes Mellitus/epidemiologia , Comorbidade , Neoplasias/epidemiologia
19.
Proc Natl Acad Sci U S A ; 119(40): e2204828119, 2022 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-36161942

RESUMO

Biased G protein-coupled receptor (GPCR) ligands, which preferentially activate G protein or ß-arrestin signaling pathways, are leading to the development of drugs with superior efficacy and reduced side effects in heart disease, pain management, and neuropsychiatric disorders. Although GPCRs are implicated in the pathophysiology of Alzheimer's disease (AD), biased GPCR signaling is a largely unexplored area of investigation in AD. Our previous work demonstrated that GPR3-mediated ß-arrestin signaling modulates amyloid-ß (Aß) generation in vitro and that Gpr3 deficiency ameliorates Aß pathology in vivo. However, Gpr3-deficient mice display several adverse phenotypes, including elevated anxiety-like behavior, reduced fertility, and memory impairment, which are potentially associated with impaired G protein signaling. Here, we generated a G protein-biased GPR3 mouse model to investigate the physiological and pathophysiological consequences of selective elimination of GPR3-mediated ß-arrestin signaling in vivo. In contrast to Gpr3-deficient mice, G protein-biased GPR3 mice do not display elevated anxiety levels, reduced fertility, or cognitive impairment. We further determined that G protein-biased signaling reduces soluble Aß levels and leads to a decrease in the area and compaction of amyloid plaques in the preclinical AppNL-G-F AD mouse model. The changes in amyloid pathology are accompanied by robust microglial and astrocytic hypertrophy, which suggest a protective glial response that may limit amyloid plaque development in G protein-biased GPR3 AD mice. Collectively, these studies indicate that GPR3-mediated G protein and ß-arrestin signaling produce discrete and separable effects and provide proof of concept for the development of safer GPCR-targeting therapeutics with more directed pharmacological action for AD.


Assuntos
Doença de Alzheimer , Amiloidose , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Modelos Animais de Doenças , Proteínas de Ligação ao GTP/metabolismo , Camundongos , Camundongos Transgênicos , Placa Amiloide/patologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , beta-Arrestinas/metabolismo
20.
J Neuroinflammation ; 19(1): 234, 2022 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-36153535

RESUMO

BACKGROUND: Research 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-ß (Aß) 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. METHODS: In 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. RESULTS: First, 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. CONCLUSIONS: Our comprehensive study provides useful transcriptomic information regarding the respective contribution of PAM and PCM across the Aß 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 Aß-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 Aß oligomer detection and in Aß-plaque initiation, with increased contribution as the disease progresses.


Assuntos
Doença de Alzheimer , Microglia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Modelos Animais de Doenças , Progressão da Doença , Humanos , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Placa Amiloide/patologia , Transcriptoma
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