%0 Journal Article %J J Alzheimers Dis %D 2023 %T The Anti-Amyloid Monoclonal Antibody Lecanemab: 16 Cautionary Notes. %A Kepp, Kasper P %A Sensi, Stefano L %A Johnsen, Kasper B %A Barrio, Jorge R %A Høilund-Carlsen, Poul F %A Neve, Rachael L %A Alavi, Abass %A Herrup, Karl %A Perry, George %A Robakis, Nikolaos K %A Vissel, Bryce %A Espay, Alberto J %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloidogenic Proteins %K Antibodies, Monoclonal %K Humans %K United States %X

After the CLARITY-AD clinical trial results of lecanemab were interpreted as positive, and supporting the amyloid hypothesis, the drug received accelerated Food and Drug Administration approval. However, we argue that benefits of lecanemab treatment are uncertain and may yield net harm for some patients, and that the data do not support the amyloid hypothesis. We note potential biases from inclusion, unblinding, dropouts, and other issues. Given substantial adverse effects and subgroup heterogeneity, we conclude that lecanemab's efficacy is not clinically meaningful, consistent with numerous analyses suggesting that amyloid-β and its derivatives are not the main causative agents of Alzheimer's disease dementia.

%B J Alzheimers Dis %V 94 %P 497-507 %8 2023 %G eng %N 2 %R 10.3233/JAD-230099 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Playing Russian Roulette with Alzheimer's Disease Patients: Do the Cognitive Benefits of Lecanemab Outweigh the Risk of Edema, Stroke and Encephalitis? %A Atwood, Craig S %A Perry, George %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognition %K Edema %K Encephalitis %K Humans %K Russia %K Stroke %X

The questionable approval of aducanumab and the recent approval of lecanemab (Leqembi; Eisai and Biogen) by the FDA has raised the issue of safety (stroke, meningitis, and encephalitis) over efficacy (slowing of cognitive decline). This communication recounts the important physiological functions of amyloid-β as a barrier protein with unique sealant and anti-pathogenic activities important for maintaining vascular integrity coupled with innate immune functions that prevent encephalitis and meningitis. The approval of a drug that obviates both of these purposive functions increases the risk of hemorrhage, edema and downstream pathogenic outcomes and should be clearly outlined to patients.

%B J Alzheimers Dis %V 92 %P 799-801 %8 2023 %G eng %N 3 %R 10.3233/JAD-230040 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Inhibition of Calpain Protects Against Tauopathy in Transgenic P301S Tau Mice. %A Liu, Mengyu %A Wang, Luwen %A Gao, Ju %A Dong, Qing %A Perry, George %A Ma, Xuemei %A Wang, Xinglong %X

Alzheimer's disease (AD) and other tauopathies are characterized by intracellular accumulation of microtubule-associated tau protein leading to neurodegeneration. Calpastatin is the endogenous inhibitor of calpain, a calcium-dependent cysteine protease that has been increasingly implicated in tauopathies. In this study, we generated a neuron specific calpastatin overexpressing knock-in transgenic mouse model and crossed it with the PS19 tauopathy mouse model expressing human P301S mutant tau protein. The forced expression of calpastatin in neurons significantly alleviated tau hyperphosphorylation measured by immunocytochemistry and immunoblot. The genetic inhibition of calpain by calpastatin also greatly suppressed characteristic hippocampal neuron loss and widespread astrogliosis and microgliosis in PS19 mice. Consistently, PS19 mice with neuronal calpastatin overexpression exhibited remarkably alleviated cognitive deficits, muscle weakness, skeletal muscle atrophy, and neuromuscular denervation, together implying the neuroprotective effects of neuronal calpastatin in PS19 mice of tauopathy. In sum, this study provides additional evidence supporting the pathological role of calpain in neurodegenerative diseases associated with tau pathology, and suggests that targeting calpain is likely a promising therapeutic approach for these devastating diseases.

%B J Alzheimers Dis %V 69 %P 1077-1087 %8 2019 Jun 18 %G eng %N 4 %R 10.3233/JAD-190281 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Tau Biology, Tauopathy, Traumatic Brain Injury, and Diagnostic Challenges. %A Castellani, Rudy J %A Perry, George %X

There is considerable interest in the pathobiology of tau protein, given its potential role in neurodegenerative diseases and aging. Tau is an important microtubule associated protein, required for the assembly of tubulin into microtubules and maintaining structural integrity of axons. Tau has other diverse cellular functions involving signal transduction, cellular proliferation, developmental neurobiology, neuroplasticity, and synaptic activity. Alternative splicing results in tau isoforms with differing microtubule binding affinity, differing representation in pathological inclusions in certain disease states, and differing roles in developmental biology and homeostasis. Tau haplotypes confer differing susceptibility to neurodegeneration. Tau phosphorylation is a normal metabolic process, critical in controlling tau's binding to microtubules, and is ongoing within the brain at all times. Tau may be hyperphosphorylated, and may aggregate as detectable fibrillar deposits in tissues, in both aging and neurodegenerative disease. The hypothesis that p-tau is neurotoxic has prompted constructs related to isomers, low-n assembly intermediates or oligomers, and the "tau prion". Human postmortem studies have elucidated broad patterns of tauopathy, with tendencies for those patterns to differ as a function of disease phenotype. However, there is extensive overlap, not only between genuine neurodegenerative diseases, but also between aging and disease. Recent studies highlight uniqueness to pathological patterns, including a pattern attributed to repetitive head trauma, although clinical correlations have been elusive. The diagnostic process for tauopathies and neurodegenerative diseases in general is challenging in many respects, and may be particularly problematic for postmortem evaluation of former athletes and military service members.

%B J Alzheimers Dis %V 67 %P 447-467 %8 2019 %G eng %N 2 %R 10.3233/JAD-180721 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Expression Profiling of Cytokine, Cholinergic Markers, and Amyloid-β Deposition in the APPSWE/PS1dE9 Mouse Model of Alzheimer's Disease Pathology. %A Reale, Marcella %A D'Angelo, Chiara %A Costantini, Erica %A Di Nicola, Marta %A Yarla, Nagnedra Sastry %A Kamal, Mohammad Amjad %A Salvador, Nieves %A Perry, George %X

BACKGROUND: Alzheimer's disease (AD), a neurodegenerative disease, is associated with dysfunction of the olfactory and the entorhinal cortex of the brain that control memory and cognitive functions and other daily activities. Pro-inflammatory cytokines, amyloid-β (Aβ), and the cholinergic system play vital roles in the pathophysiology of AD. However, the role of changes in cholinergic system components, Aβ accumulation, and cytokines in both the olfactory and entorhinal cortex is not known clearly.

OBJECTIVE: The present study is aimed to evaluate the changes of cholinergic system components, Aβ accumulation, and cytokines in both the olfactory bulb (OB) and entorhinal cortex (EC) of young and aged APPSWE/PS1dE9 transgenic (Tg) mice.

METHODS: We have explored the changes of cholinergic system components, Aβ accumulation, and expression profiling of cytokines in the OB and EC of aged APPswe transgenic mice and age-matched wild type mice using quantitative Real-Time PCR assays and immunohistochemistry techniques.

RESULTS: In aged Tg mice, a significant increase of expression of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and chemokine MCP1 (p < 0.001, p < 0.001, and p = 0.001, respectively) and a significant reduction of nAChRα4 (p = 0.048) and AChE (p = 0.023) was observed when compared with age-matched wild type mice. Higher levels of AChE and BuChE are expressed in OB and EC of the APPSWE/PS1dE9 of Tg mice. Aβ accumulation was observed in OB and EC of the APPSWE/PS1dE9 of Tg mice.

CONCLUSION: The study demonstrates the expression profiling of pro-inflammatory cytokines and cholinergic markers as well as Aβ accumulation in OB and EC of the APPSWE/PS1dE9 Tg mice. Moreover, the study also demonstrated that the APPSWE/PS1dE9 Tg mice can be useful as a mouse model to understand the role of pro-inflammatory cytokines and cholinergic markers in pathophysiology of AD.

%B J Alzheimers Dis %V 62 %P 467-476 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439355?dopt=Abstract %R 10.3233/JAD-170999 %0 Journal Article %J J Alzheimers Dis %D 2018 %T An Inducible Alpha-Synuclein Expressing Neuronal Cell Line Model for Parkinson's Disease1. %A Vasquez, Velmarini %A Mitra, Joy %A Perry, George %A Rao, K S %A Hegde, Muralidhar L %X

Altered expression of α-synuclein is linked to Parkinson's disease (PD). A major challenge to explore how the increased α-synuclein affect neurotoxicity is the lack of a suitable human neuronal cell model that mimics this scenario. Its expression in neural precursors affects their differentiation process, in addition to the neuronal adaptability and variability in maintaining a constant level of expression across passages. Here, we describe an SH-SY5Y line harboring Tet-ON SNCA cDNA cassette that allows for induction of controlled α-synuclein expression after neuronal differentiation, which can be an important tool for PD research.

%B J Alzheimers Dis %V 66 %P 453-460 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320583?dopt=Abstract %R 10.3233/JAD-180610 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Need to Separate Chronic Traumatic Encephalopathy Neuropathology from Clinical Features. %A Iverson, Grant L %A Keene, C Dirk %A Perry, George %A Castellani, Rudolph J %K Chronic Traumatic Encephalopathy %K Cognition Disorders %K Disease Progression %K Gait Disorders, Neurologic %K Humans %K Neurodegenerative Diseases %K Neuropathology %K Tremor %X

There is tremendous recent interest in chronic traumatic encephalopathy (CTE) in former collision sport athletes, civilians, and military veterans. This critical review places important recent research results into a historical context. In 2015, preliminary consensus criteria were developed for defining the neuropathology of CTE, which substantially narrowed the pathology previously reported to be characteristic. There are no agreed upon clinical criteria for diagnosis, although sets of criteria have been proposed for research purposes. A prevailing theory is that CTE is an inexorably progressive neurodegenerative disease within the molecular classification of the tauopathies. However, historical and recent evidence suggests that CTE, as it is presented in the literature, might not be pathologically or clinically progressive in a substantial percentage of people. At present, it is not known whether the emergence, course, or severity of clinical symptoms can be predicted by specific combinations of neuropathologies, thresholds for accumulation of pathology, or regional distributions of pathologies. More research is needed to determine the extent to which the neuropathology ascribed to long-term effects of neurotrauma is static, progressive, or both. Disambiguating the pathology from the broad array of clinical features that have been reported in recent studies might facilitate and accelerate research- and improve understanding of CTE.

%B J Alzheimers Dis %V 61 %P 17-28 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad170654?id=journal-of-alzheimers-disease%2Fjad170654 %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103039?dopt=Abstract %R 10.3233/JAD-170654 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Putative Gonadotropin-Releasing Hormone Agonist Therapy and Dementia: An Application of Medicare Hospitalization Claims Data. %A Smith, Mark A %A Bowen, Richard L %A Nguyen, Richard Q %A Perry, George %A Atwood, Craig S %A Rimm, Alfred A %X

BACKGROUND: Estrogen and hormone replacement therapies to reduce Alzheimer's disease (AD) have yielded conflicting results. However, this study proposes that the well-characterized increase in serum gonadotropins following menopause or andropause are accountable for the increased risk of developing AD among the elderly population.

OBJECTIVE: To determine the role of gonadotropins in the development of AD and investigate gonadotropin-releasing hormone (GnRH) agonist therapy as a potential preventative and/or disease-modifying approach to AD management.

METHODS: Male Medicare beneficiaries aged 67 to 75 and hospitalized with prostate cancer (n = 115,789) were compared to three control groups: men of the same demographics undergoing a cholecystectomy (n = 97,267), herniorrhaphy (n = 68,778), or transurethral prostatectomy (n = 267,691). A proportion of the patients hospitalized with prostate cancer were assumed to have low concentrations of serum gonadotropins and sex steroids as a result of GnRH agonist therapy, while those in the control groups were assumed to have elevated gonadotropin but lowered sex steroid levels that are associated with andropause in this age group.

RESULTS: The rates of development of select diagnoses of dementia, including AD, over a twelve-year follow-up period following surgery. When compared to control patients, men hospitalized with prostate cancer have a protection against dementia after twelve years of follow-up, with relative risks ranging from 0.48 to 0.83.

CONCLUSION: Patients with prostate cancer are treated with the GnRH analogue leuprolide acetate, our data suggest that leuprolide acetate may be therapeutic for AD via its downregulation of serum gonadotropins.

%B J Alzheimers Dis %V 63 %P 1269-1277 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782310?dopt=Abstract %R 10.3233/JAD-170847 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Rab10 Phosphorylation is a Prominent Pathological Feature in Alzheimer's Disease. %A Yan, Tingxiang %A Wang, Luwen %A Gao, Ju %A Siedlak, Sandra L %A Huntley, Mikayla L %A Termsarasab, Pichet %A Perry, George %A Chen, Shu G %A Wang, Xinglong %X

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles (NFTs), senile plaques (SPs), and a progressive loss of neuronal cells in selective brain regions. Rab10, a small Rab GTPase involved in vesicular trafficking, has recently been identified as a novel protein associated with AD. Interestingly, Rab10 is a key substrate of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine protein kinase genetically associated with the second most common neurodegenerative disease Parkinson's disease. However, the phosphorylation state of Rab10 has not yet been investigated in AD. Here, using a specific antibody recognizing LRRK2-mediated Rab10 phosphorylation at the amino acid residue threonine 73 (pRab10-T73), we performed immunocytochemical analysis of pRab10-T73 in hippocampal tissues of patients with AD. pRab10-T73 was prominent in NFTs in neurons within the hippocampus in all cases of AD examined, whereas immunoreactivity was very faint in control cases. Other characteristic AD pathological structures including granulovacuolar degeneration, dystrophic neurites and neuropil threads also contained pRab10-T73. The pRab10-T73 immunoreactivity was diminished greatly following dephosphorylation with alkaline phosphatase. pRab10-T73 was further found to be highly co-localized with hyperphosphorylated tau (pTau) in AD, and demonstrated similar pathological patterns as pTau in Down syndrome and progressive supranuclear palsy. Although pRab10-T73 immunoreactivity could be noted in dystrophic neurites surrounding SPs, SPs were largely negative for pRab10-T73. These findings indicate that Rab10 phosphorylation could be responsible for aberrations in the vesicle trafficking observed in AD leading to neurodegeneration.

%B J Alzheimers Dis %V 63 %P 157-165 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562525?dopt=Abstract %R 10.3233/JAD-180023 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Dementia Pugilistica Revisited. %A Castellani, Rudy J %A Perry, George %X

 Extensive exposure of boxers to neurotrauma in the early 20th century led to the so-called punch drunk syndrome, which was formally recognized in the medical literature in 1928. "Punch drunk" terminology was replaced by the less derisive 'dementia pugilistica' in 1937. In the early case material, the diagnosis of dementia pugilistica required neurological deficits, including slurring dysarthria, ataxia, pyramidal signs, extrapyramidal signs, memory impairment, and personality changes, although the specific clinical substrate has assumed lesser importance in recent years with a shift in focus on molecular pathogenesis. The postmortem neuropathology of dementia pugilistica has also evolved substantially over the past 90 years, from suspected concussion-related hemorrhages to diverse structural and neurofibrillary changes to geographic tauopathy. Progressive neurodegenerative tauopathy is among the prevailing theories for disease pathogenesis currently, although this may be overly simplistic. Careful examination of historical cases reveals both misdiagnoses and a likelihood that dementia pugilistica at that time was caused by cumulative structural brain injury. More recent neuropathological studies indicate subclinical and possibly static tauopathy in some athletes and non-athletes. Indeed, it is unclear from the literature whether retired boxers reach the inflection point that tends toward progressive neurodegeneration in the manner of Alzheimer's disease due to boxing. Even among historical cases with extreme levels of exposure, progressive disease was exceptional.

%B J Alzheimers Dis %V 60 %P 1209-1221 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036831?dopt=Abstract %R 10.3233/JAD-170669 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Selenoprotein S Reduces Endoplasmic Reticulum Stress-Induced Phosphorylation of Tau: Potential Role in Selenate Mitigation of Tau Pathology. %A Rueli, Rachel H L H %A Torres, Daniel J %A Dewing, Andrea S T %A Kiyohara, Arlene C %A Barayuga, Stephanie M %A Bellinger, Miyoko T %A Uyehara-Lock, Jane H %A White, Lon R %A Moreira, Paula I %A Berry, Marla J %A Perry, George %A Bellinger, Frederick P %X

Previous studies demonstrated that selenium in the form of sodium selenate reduces neurofibrillary tangle formation in Alzheimer's disease models. Hyperphosphorylation of tau, which leads to formation of neurofibrillary tangles in Alzheimer's disease, is increased by endoplasmic reticulum (ER) stress. Selenoprotein S (SelS) is part of an ER membrane complex that removes misfolded proteins from the ER as a means to reduce ER stress. Selenate, as with other forms of selenium, will increase selenoprotein expression. We therefore proposed that increased SelS expression by selenate would contribute to the beneficial actions of selenate in Alzheimer's disease. SelS expression increased with ER stress and decreased under conditions of elevated glucose concentrations in the SH-SY5Y neuronal cell line. Reducing expression of SelS with siRNA promoted cell death in response to ER stress. Selenate increased SelS expression, which significantly correlated with decreased tau phosphorylation. Restricting SelS expression during ER stress conditions increased tau phosphorylation, and also promoted aggregation of phosphorylated tau in neurites and soma. In human postmortem brain, SelS expression coincided with neurofibrillary tangles, but not with amyloid-β plaques. These results indicate that selenate can alter phosphorylation of tau by increasing expression of SelS in Alzheimer's disease and potentially other neurodegenerative disorders.

%B J Alzheimers Dis %V 55 %P 749-762 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802219?dopt=Abstract %R 10.3233/JAD-151208 %0 Journal Article %J J Alzheimers Dis %D 2017 %T TMEM230 Accumulation in Granulovacuolar Degeneration Bodies and Dystrophic Neurites of Alzheimer's Disease. %A Siedlak, Sandra L %A Jiang, Yinfei %A Huntley, Mikayla L %A Wang, Luwen %A Gao, Ju %A Xie, Fei %A Liu, Jingyi %A Su, Bo %A Perry, George %A Wang, Xinglong %X

Transmembrane Protein 230 (TMEM230) is a newly identified protein associated with Parkinson's disease (PD) found in Lewy bodies and Lewy neurites of patients with PD or dementia with Lewy body disease. However, TMEM230 has not yet been investigated in the most common neurodegenerative disorder, Alzheimer's disease (AD). Here, we demonstrate that the expression of TMEM230 is specifically increased in neurons in AD patients. Importantly, both granulovacuolar degeneration (GVD) and dystrophic neurites (DNs), two prominent characteristic pathological structures associated with AD, contain TMEM230 aggregates. TMEM230 immunoreactivity can be detected in neurofibrillary tangles-containing neurons and hyperphosphorylated tau positive DNs. TMEM230 accumulation is also noted around senile plaques. These findings identifying TMEM230 as a component of GVD and DNs suggest TMEM230 dysregulation as a likely mechanism playing an important role in the pathogenesis of AD.

%B J Alzheimers Dis %V 58 %P 1027-1033 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28527219?dopt=Abstract %R 10.3233/JAD-170190 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Fibrillar Amyloid-β Accumulation Triggers an Inflammatory Mechanism Leading to Hyperphosphorylation of the Carboxyl-Terminal End of Tau Polypeptide in the Hippocampal Formation of the 3×Tg-AD Transgenic Mouse. %A Ontiveros-Torres, Miguel Ángel %A Labra-Barrios, María Luisa %A Díaz-Cintra, Sofía %A Aguilar-Vázquez, Azucena Ruth %A Moreno-Campuzano, Samadhi %A Flores-Rodríguez, Paola %A Luna-Herrera, Claudia %A Mena, Raúl %A Perry, George %A Florán-Garduño, Benjamín %A Luna-Muñoz, José %A Luna-Arias, Juan Pedro %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Disease Models, Animal %K Female %K Hippocampus %K Humans %K Male %K Mice, Inbred C57BL %K Mice, Transgenic %K Neuroglia %K Phosphorylation %K Plaque, Amyloid %K Presenilin-1 %K Pyramidal Cells %K tau Proteins %X

Alzheimer's disease (AD) is a degenerative and irreversible disorder whose progressiveness is dependent on age. It is histopathologically characterized by the massive accumulation of insoluble forms of tau and amyloid-β (Aβ) asneurofibrillary tangles and neuritic plaques, respectively. Many studies have documented that these two polypeptides suffer several posttranslational modifications employing postmortem tissue sections from brains of patients with AD. In order to elucidate the molecular mechanisms underlying the posttranslational modifications of key players in this disease, including Aβ and tau, several transgenic mouse models have been developed. One of these models is the 3×Tg-AD transgenic mouse, carrying three transgenes encoding APPSWE, S1M146V, and TauP301L proteins. To further characterize this transgenicmouse, we determined the accumulation of fibrillar Aβ as a function of age in relation to the hyperphosphorylation patterns of TauP301L at both its N- and C-terminus in the hippocampal formation by immunofluorescence and confocal microscopy. Moreover, we searched for the expression of activated protein kinases and mediators of inflammation by western blot of wholeprotein extracts from hippocampal tissue sections since 3 to 28 months as well. Our results indicate that the presence of fibrillar Aβ deposits correlates with a significant activation of astrocytes and microglia in subiculum and CA1 regions of hippocampus. Accordingly, we also observed a significant increase in the expression of TNF-α associated to neuritic plaques and glial cells. Importantly, there is an overexpression of the stress activated protein kinases SAPK/JNK and Cdk-5 in pyramidal neurons, which might phosphorylate several residues at the C-terminus of TauP301L. Therefore, the accumulation of Aβ oligomers results in an inflammatory environment that upregulates kinases involved in hyperphosphorylation of TauP301L polypeptide.

%B J Alzheimers Dis %V 52 %P 243-69 %8 2016 03 22 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031470?dopt=Abstract %R 10.3233/JAD-150837 %0 Journal Article %J J Alzheimers Dis %D 2012 %T Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults. %A Calderón-Garcidueñas, Lilian %A Kavanaugh, Michael %A Block, Michelle %A D'Angiulli, Amedeo %A Delgado-Chávez, Ricardo %A Torres-Jardón, Ricardo %A González-Maciel, Angelica %A Reynoso-Robles, Rafael %A Osnaya, Norma %A Villarreal-Calderon, Rodolfo %A Guo, Ruixin %A Hua, Zhaowei %A Zhu, Hongtu %A Perry, George %A Diaz, Philippe %K Adolescent %K Adult %K Age Factors %K Air Pollution %K Child %K Child, Preschool %K Cohort Studies %K Down-Regulation %K Encephalitis %K Female %K Frontal Lobe %K Gene Regulatory Networks %K Humans %K Infant %K Male %K Mexico %K Phosphorylation %K Plaque, Amyloid %K Prions %K tau Proteins %K Young Adult %X

Air pollution exposures have been linked to neuroinflammation and neuropathology. Autopsy samples of the frontal cortex from control (n = 8) and pollution-exposed (n = 35) children and young adults were analyzed by RT-PCR (n = 43) and microarray analysis (n = 12) for gene expression changes in oxidative stress, DNA damage signaling, NFκB signaling, inflammation, and neurodegeneration pathways. The effect of apolipoprotein E (APOE) genotype on the presence of protein aggregates associated with Alzheimer's disease (AD) pathology was also explored. Exposed urbanites displayed differential (>2-fold) regulation of 134 genes. Forty percent exhibited tau hyperphosphorylation with pre-tangle material and 51% had amyloid-β (Aβ) diffuse plaques compared with 0% in controls. APOE4 carriers had greater hyperphosphorylated tau and diffuse Aβ plaques versus E3 carriers (Q = 7.82, p = 0.005). Upregulated gene network clusters included IL1, NFκB, TNF, IFN, and TLRs. A 15-fold frontal down-regulation of the prion-related protein (PrP(C)) was seen in highly exposed subjects. The down-regulation of the PrP(C) is critical given its important roles for neuroprotection, neurodegeneration, and mood disorder states. Elevation of indices of neuroinflammation and oxidative stress, down-regulation of the PrP(C) and AD-associated pathology are present in young megacity residents. The inducible regulation of gene expression suggests they are evolving different mechanisms in an attempt to cope with the constant state of inflammation and oxidative stress related to their environmental exposures. Together, these data support a role for air pollution in CNS damage and its impact upon the developing brain and the potential etiology of AD and mood disorders.

%B J Alzheimers Dis %V 28 %P 93-107 %8 2012 %G eng %N 1 %R 10.3233/JAD-2011-110722