RESUMO

This Review emphasizes the impact of APOE4-the most significant genetic risk factor for Alzheimer's disease (AD)-on peripheral and neural effects starting in childhood. We discuss major mechanistic players associated with the APOE alleles' effects in humans to understand their impact from conception through all life stages and the importance of detrimental, synergistic environmental exposures. APOE4 influences AD pathogenesis, and exposure to fine particulate matter (PM2.5), manufactured nanoparticles (NPs), and ultrafine particles (UFPs) associated with combustion and friction processes appear to be major contributors to cerebrovascular dysfunction, neuroinflammation, and oxidative stress. In the context of outdoor and indoor PM pollution burden-as well as Fe, Ti, and Al alloys; Hg, Cu, Ca, Sn, and Si UFPs/NPs-in placenta and fetal brain tissues, urban APOE3 and APOE4 carriers are developing AD biological disease hallmarks (hyperphosphorylated-tau (P-tau) and amyloid beta 42 plaques (Aß42)). Strikingly, for Metropolitan Mexico City (MMC) young residents ≤ 40 y, APOE4 carriers have 4.92 times higher suicide odds and 23.6 times higher odds of reaching Braak NFT V stage versus APOE4 non-carriers. The National Institute on Aging and Alzheimer's Association (NIA-AA) framework could serve to test the hypothesis that UFPs and NPs are key players for oxidative stress, neuroinflammation, protein aggregation and misfolding, faulty complex protein quality control, and early damage to cell membranes and organelles of neural and vascular cells. Noninvasive biomarkers indicative of the P-tau and Aß42 abnormal protein deposits are needed across the disease continuum starting in childhood. Among the 21.8 million MMC residents, we have potentially 4 million APOE4 carriers at accelerated AD progression. These APOE4 individuals are prime candidates for early neuroprotective interventional trials. APOE4 is key in the development of AD evolving from childhood in highly polluted urban centers dominated by anthropogenic and industrial sources of pollution. APOE4 subjects are at higher early risk of AD development, and neuroprotection ought to be implemented. Effective reductions of PM2.5, UFP, and NP emissions from all sources are urgently needed. Alzheimer's Disease prevention ought to be at the core of the public health response and physicians-scientist minority research be supported.

Assuntos

Poluição do Ar , Doença de Alzheimer , Apolipoproteína E4 , Material Particulado , Suicídio , Humanos , Poluição do Ar/efeitos adversos , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides , Apolipoproteína E4/genética , Encéfalo/patologia , Cidades/epidemiologia , Interação Gene-Ambiente , Heterozigoto , México/epidemiologia , Doenças Neuroinflamatórias/etiologia , Doenças Neuroinflamatórias/genética , Material Particulado/efeitos adversos , Suicídio/estatística & dados numéricos

RESUMO

Environmental exposures to fine particulate matter (PM2.5) and ultrafine particle matter (UFPM) are associated with overlapping Alzheimer's, Parkinson's and TAR DNA-binding protein 43 (TDP-43) hallmark protein pathologies in young Metropolitan Mexico City (MMC) urbanites. We measured CSF concentrations of TDP-43 in 194 urban residents, including 92 MMC children aged 10.2 ± 4.7 y exposed to PM2.5 levels above the USEPA annual standard and to high UFPM and 26 low pollution controls (11.5 ± 4.4 y); 43 MMC adults (42.3 ± 15.9 y) and 14 low pollution adult controls (33.1 ± 12.0 y); and 19 amyotrophic lateral sclerosis (ALS) patients (52.4 ± 14.1 y). TDP-43 neuropathology and cisternal CSF data from 20 subjects­15 MMC (41.1 ± 18.9 y) and 5 low pollution controls (46 ± 16.01 y)­were included. CSF TDP-43 exponentially increased with age (p < 0.0001) and it was higher for MMC residents. TDP-43 cisternal CSF levels of 572 ± 208 pg/mL in 6/15 MMC autopsy cases forecasted TDP-43 in the olfactory bulb, medulla and pons, reticular formation and motor nuclei neurons. A 16 y old with TDP-43 cisternal levels of 1030 pg/mL exhibited TDP-43 pathology and all 15 MMC autopsy cases exhibited AD and PD hallmarks. Overlapping TDP-43, AD and PD pathologies start in childhood in urbanites with high exposures to PM2.5 and UFPM. Early, sustained exposures to PM air pollution represent a high risk for developing brains and MMC UFPM emissions sources ought to be clearly identified, regulated, monitored and controlled. Prevention of deadly neurologic diseases associated with air pollution ought to be a public health priority and preventive medicine is key.

RESUMO

BACKGROUND: Protein aggregates are pathological hallmarks of many neurodegenerative diseases, however the physiopathological role of these aggregates is not fully understood. Protein quality control has a pivotal role for protein homeostasis and depends on specific chaperones. The co-chaperone BAG2 can target phosphorylated Tau for degradation by an ubiquitin-independent pathway, although its possible role in autophagy was not yet elucidated. In view of this, the aim of the present study was to investigate the association among protein aggregation, autophagy and BAG2 levels in cultured cells from hippocampus and locus coeruleus as well as in SH-SY5Y cell line upon different protein aggregation scenarios induced by rotenone, which is a flavonoid used as pesticide and triggers neurodegeneration. METHODS AND RESULTS: The present study showed that rotenone exposure at 0.3 nM for 48 h impaired autophagy prior to Tau phosphorylation at Ser199/202 in hippocampus but not in locus coeruleus cells, suggesting that distinct neuron cells respond differently to rotenone toxicity. Rotenone induced Tau phosphorylation at Ser199/202, together with a decrease in the endogenous BAG2 protein levels in SH-SY5Y and hippocampus cell culture, which indicates that rotenone and Tau hyperphosphorylation can affect this co-chaperone. Finally, it has been shown that BAG2 overexpression, increased p62/SQSTM1 levels in cells from hippocampus and locus coeruleus, stimulated LC3II recycling as well as prevented the raise of phosphorylated Tau at Ser199/202 in hippocampus. CONCLUSIONS: Results demonstrate a possible role for BAG2 in degradation pathways of specific substrates and its importance for the study of cellular aspects of neurodegenerative diseases.

Assuntos

Neuroblastoma , Rotenona , Humanos , Chaperonas Moleculares/metabolismo , Agregados Proteicos , Rotenona/farmacologia , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Proteínas tau/metabolismo

RESUMO

Fine particulate air pollution (PM2.5) exposures are linked with Alzheimer's and Parkinson's diseases (AD,PD). AD and PD neuropathological hallmarks are documented in children and young adults exposed lifelong to Metropolitan Mexico City air pollution; together with high frontal metal concentrations (especially iron)-rich nanoparticles (NP), matching air pollution combustion- and friction-derived particles. Here, we identify aberrant hyperphosphorylated tau, ɑ synuclein and TDP-43 in the brainstem of 186 Mexico City 27.29 ± 11.8y old residents. Critically, substantia nigrae (SN) pathology seen in mitochondria, endoplasmic reticulum and neuromelanin (NM) is co-associated with the abundant presence of exogenous, Fe-, Al- and Ti-rich NPs.The SN exhibits early and progressive neurovascular unit damage and mitochondria and NM are associated with metal-rich NPs including exogenous engineered Ti-rich nanorods, also identified in neuroenteric neurons. Such reactive, cytotoxic and magnetic NPs may act as catalysts for reactive oxygen species formation, altered cell signaling, and protein misfolding, aggregation and fibril formation. Hence, pervasive, airborne and environmental, metal-rich and magnetic nanoparticles may be a common denominator for quadruple misfolded protein neurodegenerative pathologies affecting urbanites from earliest childhood. The substantia nigrae is a very early target and the gastrointestinal tract (and the neuroenteric system) key brainstem portals. The ultimate neural damage and neuropathology (Alzheimer's, Parkinson's and TDP-43 pathology included) could depend on NP characteristics and the differential access and targets achieved via their portals of entry. Thus where you live, what air pollutants you are exposed to, what you are inhaling and swallowing from the air you breathe,what you eat, how you travel, and your occupational longlife history are key. Control of NP sources becomes critical.

Assuntos

Doença de Alzheimer , Nanopartículas de Magnetita , Nanotubos , Tronco Encefálico , Criança , Cidades , Trato Gastrointestinal , Humanos , México , Agregados Proteicos , Titânio/toxicidade , Adulto Jovem , alfa-Sinucleína

RESUMO

Exposures to fine particulate matter (PM2.5) and ozone (O3) above USEPA standards are associated with Alzheimer's disease (AD) risk. Metropolitan Mexico City (MMC) youth have life time exposures to PM2.5 and O3 above standards. We focused on MMC residents ≤30 years and reviewed 134 consecutive autopsies of subjects age 20.03 ± 6.38 y (range 11 months to 30 y), the staging of Htau and ß amyloid, the lifetime cumulative PM2.5 (CPM 2.5) and the impact of the Apolipoprotein E (APOE) 4 allele, the most prevalent genetic risk for AD. We also reviewed the results of the Montreal Cognitive Assessment (MoCA) and the brainstem auditory evoked potentials (BAEPs) in clinically healthy young cohorts. Mobile sources, particularly from non-regulated diesel vehicles dominate the MMC pollutant emissions exposing the population to PM2.5 concentrations above WHO and EPA standards. Iron-rich,magnetic, highly oxidative, combustion and friction-derived nanoparticles (CFDNPs) are measured in the brain of every MMC resident. Progressive development of Alzheimer starts in childhood and in 99.25% of 134 consecutive autopsies ≤30 years we can stage the disease and its progression; 66% of ≤30 years urbanites have cognitive impairment and involvement of the brainstem is reflected by auditory central dysfunction in every subject studied. The average age for dementia using MoCA is 20.6 ± 3.4 y. APOE4 vs 3 carriers have 1.26 higher odds of committing suicide. PM2.5 and CFDNPs play a key role in the development of neuroinflammation and neurodegeneration in young urbanites. A serious health crisis is in progress with social, educational, judicial, economic and overall negative health impact for 25 million residents. Understanding the neural circuitry associated with the earliest cognitive and behavioral manifestations of AD is needed. Air pollution control should be prioritised-including the regulation of diesel vehicles- and the first two decades of life ought to be targeted for neuroprotective interventions. Defining paediatric environmental, nutritional, metabolic and genetic risk factor interactions is a multidisciplinary task of paramount importance to prevent Alzheimer's disease. Current and future generations are at risk.

Assuntos

Poluentes Atmosféricos , Poluição do Ar , Doença de Alzheimer , Adolescente , Poluentes Atmosféricos/toxicidade , Doença de Alzheimer/epidemiologia , Criança , Cidades , Humanos , México/epidemiologia , Material Particulado

RESUMO

A major impediment in early diagnosis of Alzheimer's disease (AD) is the lack of robust non-invasive biomarkers of early brain dysfunction. Metropolitan Mexico City (MMC) children and young adults show hyperphosphorylated tau, amyloid-ß, and α-synuclein within auditory and vestibular nuclei and marked dysmorphology in the ventral cochlear nucleus and superior olivary complex. Based on early involvement of auditory brainstem centers, we believe brainstem auditory evoked potentials can provide early AD biomarkers in MMC young residents. We measured brainstem auditory evoked potentials in MMC clinically healthy children (8.52±3.3 years) and adults (21.08±3.0 years, 42.48±8.5 years, and 71.2±6.4 years) compared to clean air controls (6.5±0.7 years) and used multivariate analysis adjusting for age, gender, and residency. MMC children had decreased latency to wave I, delays in waves III and V, and longer latencies for interwave intervals, consistent with delayed central conduction time of brainstem neural transmission. In sharp contrast, young adults have significantly shortened interwave intervals I-III and I-V. By the 5th decade, wave V and interval I-V were significantly shorter, while the elderly cohort had significant delay in mean latencies and interwave intervals. Compensatory plasticity, increased auditory gain, cochlear synaptopathy, neuroinflammation, and AD continuum likely play a role in the evolving distinct auditory pathology in megacity urbanites. Understanding auditory central and peripheral dysfunction in the AD continuum evolving and progressing in pediatric and young adult populations may shed light on the complex mechanisms of AD development and help identify strong noninvasive biomarkers. AD evolving from childhood in air pollution environments ought to be preventable.

Assuntos

Poluição do Ar/efeitos adversos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/epidemiologia , Vias Auditivas/fisiopatologia , Potenciais Evocados Auditivos/fisiologia , População Urbana/tendências , Adolescente , Adulto , Idoso , Doença de Alzheimer/fisiopatologia , Criança , Feminino , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem

RESUMO

Inflammation has been suggested to play early and perhaps causative roles in Alzheimer's disease (AD) pathogenesis possibly in part by the overactivation of the aspartic acid protease named ß-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), which is responsible for the ß-amyloid cascade. We have described that BACE1 is involved in the lysophosphatidylethanolamine (LPE) (18:1/20:4/22:6) upregulation associated with tauopathy and inflammation signaling (cPLA2/arachidonic acid/COX2) in a triple transgenic model of Alzheimer's disease, where BACE1 silencing reversed the imbalanced profile and produced cognitive function improvement. In this study, we analyze the role of cPLA2 and desaturases (SCD1, FAD6) in the BACE1 knockdown-induced protective action under a glutamate excitotoxicity model. Glutamate (125 µM) produced hyperphosphorylation of tau in cortical primary cultures along with increased apoptotic nuclei, LDH release, and cPLA2 expression, which were all reversed by BACE1-KD. This beneficial effect was reinforced by the silencing of cPLA2 but attenuated by the reduction in SCD1 and partially attenuated by the reduction in FAD6. Inversely, overexpression SCD1 and FAD6 recovered the neuroprotective effect produced by BACE1-KD, which was not achieved by the overexpression of each desaturase alone. These findings suggest that the hyperphosphorylation of tau and the creation of a pro-inflammatory cell environment are blocked in a desaturase-dependent manner by targeting BACE1.

Assuntos

Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Fosfolipases A2 do Grupo IV/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/etiologia , Secretases da Proteína Precursora do Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Apoptose/genética , Ácido Aspártico Endopeptidases/genética , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Potenciais Pós-Sinápticos Excitadores , Técnicas de Silenciamento de Genes , Ácido Glutâmico/metabolismo , Fosfolipases A2 do Grupo IV/genética , Neurônios/metabolismo , Fosforilação/genética , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Wistar , Estearoil-CoA Dessaturase/genética , Proteínas tau/toxicidade

RESUMO

There is growing evidence that air pollution is a risk factor for a number of neurodegenerative diseases, most notably Alzheimer's (AD) and Parkinson's (PD). It is generally assumed that the pathology of these diseases arises only later in life and commonly begins within olfactory eloquent pathways prior to the onset of the classical clinical symptoms. The present study demonstrates that chronic exposure to high levels of air pollution results in AD- and PD-related pathology within the olfactory bulbs of children and relatively young adults ages 11 months to 40 years. The olfactory bulbs (OBs) of 179 residents of highly polluted Metropolitan Mexico City (MMC) were evaluated for AD- and alpha-synuclein-related pathology. Even in toddlers, hyperphosphorylated tau (hTau) and Lewy neurites (LN) were identified in the OBs. By the second decade, 84% of the bulbs exhibited hTau (48/57), 68% LNs and vascular amyloid (39/57) and 36% (21/57) diffuse amyloid plaques. OB active endothelial phagocytosis of red blood cell fragments containing combustion-derived nanoparticles (CDNPs) and the neurovascular unit damage were associated with myelinated and unmyelinated axonal damage. OB hTau neurites were associated mostly with pretangle stages 1a and 1b in subjects ≤ 20 years of age, strongly suggesting olfactory deficits could potentially be an early guide of AD pretangle subcortical and cortical hTau. APOE4 versus APOE3 carriers were 6-13 times more likely to exhibit OB vascular amyloid, neuronal amyloid accumulation, alpha-synuclein aggregates, hTau neurofibrillary tangles, and neurites. Remarkably, APOE4 carriers were 4.57 times more likely than non-carriers to die by suicide. The present findings, along with previous data that over a third of clinically healthy MMC teens and young adults exhibit low scores on an odor identification test, support the concept that olfactory testing may aid in identifying young people at high risk for neurodegenerative diseases. Moreover, results strongly support early neuroprotective interventions in fine particulate matter (PM2.5) and CDNP's exposed individuals ≤ 20 years of age, and the critical need for air pollution control.

Assuntos

Poluição do Ar/efeitos adversos , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Bulbo Olfatório/patologia , Suicídio , alfa-Sinucleína/genética , Adolescente , Adulto , Doença de Alzheimer/genética , Pré-Escolar , Cidades , Humanos , Lactente , México , Adulto Jovem

RESUMO

Mexico City (MC) young residents are exposed to high levels of fine particulate matter (PM2.5), have high frontal concentrations of combustion-derived nanoparticles (CDNPs), accumulation of hyperphosphorylated aggregated α-synuclein (α-Syn) and early Parkinson's disease (PD). Swallowed CDNPs have easy access to epithelium and submucosa, damaging gastrointestinal (GI) barrier integrity and accessing the enteric nervous system (ENS). This study is focused on the ENS, vagus nerves and GI barrier in young MC v clean air controls. Electron microscopy of epithelial, endothelial and neural cells and immunoreactivity of stomach and vagus to phosphorylated ɑ-synuclein Ser129 and Hyperphosphorylated-Tau (Htau) were evaluated and CDNPs measured in ENS. CDNPs were abundant in erythrocytes, unmyelinated submucosal, perivascular and intramuscular nerve fibers, ganglionic neurons and vagus nerves and associated with organelle pathology. ɑSyn and Htau were present in 25/27 MC gastric,15/26 vagus and 18/27 gastric and 2/26 vagus samples respectively. We strongly suggest CDNPs are penetrating and damaging the GI barrier and reaching preganglionic parasympathetic fibers and the vagus nerve. This work highlights the potential role of CDNPs in the neuroenteric hyperphosphorylated ɑ-Syn and tau pathology as seen in Parkinson and Alzheimer's diseases. Highly oxidative, ubiquitous CDNPs constitute a biologically plausible path into Parkinson's and Alzheimer's pathogenesis.

Assuntos

Poluentes Atmosféricos/toxicidade , Intestino Delgado/efeitos dos fármacos , Nanopartículas/toxicidade , Nervo Vago/efeitos dos fármacos , Emissões de Veículos/toxicidade , Adolescente , Adulto , Animais , Biomarcadores/análise , Criança , Cidades , Cães , Feminino , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Mucosa Intestinal/ultraestrutura , Intestino Delgado/patologia , Intestino Delgado/ultraestrutura , Masculino , México , Microscopia Eletrônica de Transmissão , Fosforilação , RNA Mensageiro/análise , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/patologia , Junções Íntimas/ultraestrutura , Nervo Vago/metabolismo , Nervo Vago/ultraestrutura , Adulto Jovem , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo

RESUMO

Physical exercise can attenuate the effects of aging on the central nervous system by increasing the expression of neurotrophins such as brain-derived neurotrophic factor (BDNF), which promotes dendritic branching and enhances synaptic machinery, through interaction with its receptor TrkB. TrkB receptors are synthesized in the cell body and are transported to the axonal terminals and anchored to plasma membrane, through SLP1, CRMP2 and Rab27B, associated with KIF1B. Retrograde trafficking is made by EDH-4 together with dynactin and dynein molecular motors. In the present study it was found that early neurodegeneration is accompanied by decrease in BDNF signaling, in the absence of hyperphosphorylated tau aggregation, in hippocampus of 11 months old Lewis rats exposed to rotenone. It was also demonstrated that moderate physical activity (treadmill running, during 6 weeks, concomitant to rotenone exposure) prevents the impairment of BDNF system in aged rats, which may contribute to delay neurodegeneration. In conclusion, decrease in BDNF and TrkB vesicles occurs before large aggregate-like p-Tau are formed and physical activity applied during early neurodegeneration may be of relevance to prevent BDNF system decay.

RESUMO

Protein aggregation is an important feature of neurodegenerative disorders. In Alzheimer's disease (AD) protein aggregates are composed of hyperphosphorylated Tau and amyloid beta peptide (Aß). Despite the involvement and identification of the molecular composition of these aggregates, their role in AD pathophysiology is not fully understood. However, depositions of these insoluble aggregates are typically reported as pathogenic and toxic for cell homeostasis. New evidences suggest that the deposition of these aggregates is a protective mechanism that preserves cell from toxic insults associated with the early stages of neurodegenerative diseases. To better understand the biological role of the protein aggregation with regard its effects in cellular homeostasis, the present study investigated the role of insoluble Tau and Tau aggregates on crucial cellular parameters such as redox homeostasis, proteasome activity and autophagy in hippocampal cell cultures and hippocampus of aged Lewis rats using a rotenone-induced aggregation model. Neurons were exposed to rotenone in different concentrations and exposure times aiming to determine the interval required for Tau aggregation. Our experimental design allowed us to demonstrate that rotenone exposure induces Tau hyperphosphorylation and aggregation in a concentration and time-dependent manner. Oxidative stress triggered by rotenone exposure was observed with the absence of Tau aggregates and was reduced or absent when Tau aggregates were present. This reduction of oxidative stress along with the presence of insoluble Tau was independent of alterations in antioxidant enzymes activities or cell death. In addition, rotenone induced oxidative stress was mainly associated with decrease in proteasome activity and autophagy flux. Conversely, when insoluble Tau appeared, autophagy turns to be overactivated while proteasome activity remained low. Our studies significantly advance the understanding that Tau aggregation might exert protective cellular effects, at least briefly, when neurons are facing neurodegeneration stimulus. We believe that our data add more complexity for the understanding of protein aggregation role in AD etiology.