Combinatorial model of amyloid ß and tau reveals synergy between amyloid deposits and tangle formation.

AIMS: To illuminate the pathological synergy between Aß and tau leading to emergence of neurofibrillary tangles (NFT) in Alzheimer's disease (AD), here, we have performed a comparative neuropathological study utilising three distinctive variants of human tau (WT tau, P301L mutant tau and S320F mutant tau). Previously, in non-transgenic mice, we showed that WT tau or P301L tau does not form NFT while S320F tau can spontaneously aggregate into NFT, allowing us to test the selective vulnerability of these different tau conformations to the presence of Aß plaques. METHODS: We injected recombinant AAV-tau constructs into neonatal APP transgenic TgCRND8 mice or into 3-month-old TgCRND8 mice; both cohorts were aged 3 months post injection. This allowed us to test how different tau variants synergise with soluble forms of Aß (pre-deposit cohort) or with frank Aß deposits (post-deposit cohort). RESULTS: Expression of WT tau did not produce NFT or altered Aß in either cohort. In the pre-deposit cohort, S320F tau induced Aß plaque deposition, neuroinflammation and synaptic abnormalities, suggesting that early tau tangles affect the amyloid cascade. In the post-deposit cohort, contemporaneous expression of S320F tau did not exacerbate amyloid pathology, showing a dichotomy in Aß-tau synergy based on the nature of Aß. P301L tau produced NFT-type inclusions in the post-deposit cohort, but not in the pre-deposit cohort, indicating pathological synergy with pre-existing Aß deposits. CONCLUSIONS: Our data show that different tau mutations representing specific folding variants of tau synergise with Aß to different extents, depending on the presence of cerebral deposits.

MhcII Regulates Transmission of α-Synuclein-Seeded Pathology in Mice.

MHCII molecules, expressed by professional antigen-presenting cells (APCs) such as T cells and B cells, are hypothesized to play a key role in the response of cellular immunity to α-synuclein (α-syn). However, the role of cellular immunity in the neuroanatomic transmission of α-syn pre-formed fibrillar (PFF) seeds is undetermined. To illuminate whether cellular immunity influences the transmission of α-syn seeds from the periphery into the CNS, we injected preformed α-syn PFFs in the hindlimb of the Line M83 transgenic mouse model of synucleinopathy lacking MhcII. We showed that a complete deficiency in MhcII accelerated the appearance of seeded α-syn pathology and shortened the lifespan of the PFF-seeded M83 mice. To characterize whether B-cell and T-cell inherent MhcII function underlies this accelerated response to PFF seeding, we next injected α-syn PFFs in Rag1-/- mice which completely lacked these mature lymphocytes. There was no alteration in the lifespan or burden of endstage α-syn pathology in the PFF-seeded, Rag1-deficient M83+/- mice. Together, these results suggested that MhcII function on immune cells other than these classical APCs is potentially involved in the propagation of α-syn in this model of experimental synucleinopathy. We focused on microglia next, finding that while microglial burden was significantly upregulated in PFF-seeded, MhcII-deficient mice relative to controls, the microglial activation marker Cd68 was reduced in these mice, suggesting that these microglia were not responsive. Additional analysis of the CNS showed the early appearance of the neurotoxic astrocyte A1 signature and the induction of the Ifnγ-inducible anti-viral response mediated by MhcI in the MhcII-deficient, PFF-seeded mice. Overall, our data suggest that the loss of MhcII function leads to a dysfunctional response in non-classical APCs and that this response could potentially play a role in determining PFF-induced pathology. Collectively, our results identify the critical role of MhcII function in synucleinopathies induced by α-syn prion seeds.

Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy.

Understanding the biological functions of tau variants can illuminate differential etiologies of Alzheimer's disease (AD) and primary tauopathies. Though the end-stage neuropathological attributes of AD and primary tauopathies are similar, the etiology and behavioral outcomes of these diseases follow unique and divergent trajectories. To study the divergent physiological properties of tau variants on a uniform immunogenetic background, we created somatic transgenesis CNS models of tauopathy utilizing neonatal delivery of adeno-associated viruses expressing wild-type (WT) or mutant tau in non-transgenic mice. We selected four different tau variants-WT tau associated with AD, P301L mutant tau associated with frontotemporal dementia (FTD), S320F mutant tau associated with Pick's disease and a combinatorial approach using P301L/S320F mutant tau. CNS-targeted expression of WT and P301L mutant tau results in robust tau hyperphosphorylation without tangle pathology, gradually developing age-progressive memory deficits. In contrast, the S320F variant, especially in combination with P301L, produces an AD-type tangle pathology, focal neuroinflammation and memory impairment on an accelerated time scale. Using the doubly mutated P301L/S320F tau variant, we demonstrate that combining different mutations can have an additive effect on neuropathologies and associated co-morbidities, possibly hinting at involvement of unique functional pathways. Importantly, we also show that overexpression of wild-type tau as well as an FTD-associated tau variant can lead to cognitive deficits even in the absence of tangles. Together, our data highlights the synergistic neuropathologies and associated cognitive and synaptic alterations of the combinatorial tau variant leading to a robust model of tauopathy.

Deletion of Abi3/Gngt2 influences age-progressive amyloid ß and tau pathologies in distinctive ways.

BACKGROUND: The S209F variant of Abelson Interactor Protein 3 (ABI3) increases risk for Alzheimer's disease (AD), but little is known about its function in relation to AD pathogenesis. METHODS: Here, we use a mouse model that is deficient in Abi3 locus to study how the loss of function of Abi3 impacts two cardinal neuropathological hallmarks of AD-amyloid ß plaques and tau pathology. Our study employs extensive neuropathological and transcriptomic characterization using transgenic mouse models and adeno-associated virus-mediated gene targeting strategies. RESULTS: Analysis of bulk RNAseq data confirmed age-progressive increase in Abi3 levels in rodent models of AD-type amyloidosis and upregulation in AD patients relative to healthy controls. Using RNAscope in situ hybridization, we localized the cellular distribution of Abi3 in mouse and human brains, finding that Abi3 is expressed in both microglial and non-microglial cells. Next, we evaluated Abi3-/- mice and document that both Abi3 and its overlapping gene, Gngt2, are disrupted in these mice. Using multiple transcriptomic datasets, we show that expression of Abi3 and Gngt2 are tightly correlated in rodent models of AD and human brains, suggesting a tight co-expression relationship. RNAseq of the Abi3-Gngt2-/- mice revealed upregulation of Trem2, Plcg2, and Tyrobp, concomitant with induction of an AD-associated neurodegenerative signature, even in the absence of AD-typical neuropathology. In APP mice, loss of Abi3-Gngt2 resulted in a gene dose- and age-dependent reduction in Aß deposition. Additionally, in Abi3-Gngt2-/- mice, expression of a pro-aggregant form of human tau exacerbated tauopathy and astrocytosis. Further, using in vitro culture assays, we show that the AD-associated S209F mutation alters the extent of ABI3 phosphorylation. CONCLUSIONS: These data provide an important experimental framework for understanding the role of Abi3-Gngt2 function and early inflammatory gliosis in AD. Our studies also demonstrate that inflammatory gliosis could have opposing effects on amyloid and tau pathology, highlighting the unpredictability of targeting immune pathways in AD.

Il-10 signaling reduces survival in mouse models of synucleinopathy.

Parkinson's disease (PD) and related synucleinopathies are characterized by chronic neuroinflammation leading to the premise that anti-inflammatory therapies could ameliorate synucleinopathy and associated sequelae. To test this idea, we used recombinant adeno-associated viruses (AAV) to express the anti-inflammatory cytokine, Interleukin (Il)-10, in Line M83 transgenic mice that expresses the PD-associated A53T mutant human α-synuclein (αSyn). Contrary to our expectations, we observed that intraspinal Il-10 expression initiated at birth upregulated microgliosis and led to early death in homozygous M83+/+ mice. We further observed that Il-10 preconditioning led to reduced lifespan in the hemizygous M83+/- mice injected with preformed αSyn aggregates in hindlimb muscles. To determine the mechanistic basis for these adverse effects, we took advantage of the I87A variant Il-10 (vIl-10) that has predominantly immunosuppressive properties. Sustained intraspinal expression of vIl-10 in preformed αSyn-aggregate seeded M83+/- mice resulted in earlier death, accelerated αSyn pathology, pronounced microgliosis, and increased apoptosis compared to control mice. AAV-vIl-10 expression robustly induced p62 and neuronal LC3B accumulation in these mice, indicating that Il-10 signaling mediated preconditioning of the neuraxis can potentially exacerbate αSyn accumulation through autophagy dysfunction in the neurons. Together, our data demonstrate unexpected adverse effects of both Il-10 and its immunosuppressive variant, vIl-10, in a mouse model of PD, highlighting the pleiotropic functions of immune mediators and their complex role in non-cell autonomous signaling in neurodegenerative proteinopathies.

Intracerebral Expression of AAV-APOE4 Is Not Sufficient to Alter Tau Burden in Two Distinct Models of Tauopathy.

Apolipoprotein E4 (APOE4) is the major genetic risk factor for sporadic Alzheimer's disease (AD), which is characterized by amyloid ß (Aß) plaques and tau tangles. Though the role of APOE4 in Aß pathogenesis has been mechanistically defined in rodent models, much less is known regarding the relationship of APOE4 to tau pathogenesis. Recent studies have indicated a possible correlation between APOE isoform-dependent alterations in tau pathology and neurodegeneration. To explore whether neuronal expression of APOE4 triggers tauopathy, here we delivered adeno-associated viruses (AAV) expressing human APOE4 in two different models of tauopathy-rTg4510 and PS19 lines. Intracerebroventricular delivery of AAV-APOE4 in neonatal rTg4510 and PS19 mice resulted in increased APOE4 protein in neurons but did not result in altered phosphorylated tau burden, pretangle tau pathology, or silver-positive tangle pathology. Biochemical analysis of synaptic proteins did not reveal substantial alterations. Our results indicate that over-expression of APOE4 in neurons, using an AAV-mediated approache, is not sufficient to accelerate or otherwise alter the inherent tau pathology that occurs in mice overexpressing mutant human tau.

Hepatic abscess induced by foreign body: case report and literature review.

Hepatic abscess due to perforation of the gastrointestinal tract caused by ingested foreign bodies is uncommon. Pre-operative diagnosis is difficult as patients are often unaware of the foreign body ingestion and symptoms and imagiology are usually non-specific. The authors report a case of 62-year-old woman who was admitted with fever and abdominal pain. Further investigation revealed hepatic abscess, without resolution despite antibiotic therapy. A liver abscess resulting from perforation and intra-hepatic migration of a bone coming from the pilorum was diagnosed by surgery. The literature concerning foreign body-induced perforation of the gastrointestinal tract complicated by liver abscess is reviewed.

Burkholderia contaminans Colonization from Contaminated Liquid Docusate (Colace) in a Immunocompetent Adult with Legionnaire's Disease: Infection Control Implications and the Potential Role of Candida pellucosa.

Objective:B. contaminans was cultured from respiratory secretions and liquid docusate (Colace) in a Neurosurgical Intensive Care Unit (NICU) patient with community-acquired Legionnaire's disease but not from another bottle given to the patient. Unexpectedly, C. pelliculosa was cultured from two bottles, but not the B. contaminans bottle or respiratory secretions. Methods:B. cepacia, later identified as B. contaminans, was cultured from a bottle of liquid docusate (Colace) dispensed to a non-cystic fibrosis patient. His respiratory secretions were colonized with B. contaminans. Results: Eradication of B. contaminans colonization in the patient's respiratory secretions was attempted. With levofloxacin, B. contaminans developed multidrug resistance (MDR). Subsequent TMP-SMX therapy did not result in further MDR. Nine other ICU patients were given docusate from the same lot, but there were no other B. contaminans isolates. Conclusion:B. contaminans colonization of respiratory secretion may be difficult to eliminate. The significance of C. pelliculosa cultured from liquid docusate (Colace) remains to be elucidated. In this case, it appeared that B. contaminans may have inhibited the growth of C. pelliculosa in the same bottle. Others should be alerted to the possibility that C. pelliculosa may be present in B. contaminans-contaminated lots of liquid docusate (Colace).

Hyperleptinemia as a risk factor for high blood pressure in the elderly.

CONTEXT: Studies have demonstrated that high serum leptin levels are associated with aging. However, we do not know whether hyperleptinemia is a relevant risk factor for high blood pressure (HBP) in the elderly. OBJECTIVE: To determine the relationship between hyperleptinemia and HBP in the elderly. DESIGN: A comparative cross-sectional study was carried out in a convenience sample of 70 healthy elderly persons comprising 46 women (mean age, 67 +/- 5.8 years) and 24 men (mean age, 73 +/- 7.5 years), and a group of 91 elderly persons with HBP, comprising 62 women (mean age, 67 +/- 8.2 years) and 29 men (mean age, 70 +/- 0.3 years). We measured serum leptin levels through the radioimmunoassay method. RESULTS: The elderly subjects with HBP had significantly higher leptin levels than the healthy elderly subjects (P = .02). Furthermore, in female elderly subjects we observed a statistically significant correlation between systolic blood pressure and leptin (r = 0.37, P = .003), as well as systolic blood pressure and age (r = 0.29, P = .02), but not with diastolic blood pressure. In male elderly subjects, there was no correlation between leptin and systolic blood pressure or leptin and diastolic blood pressure. However, hyperleptinemia as risk factor for HBP was nearly 5 times higher in men than in women (men, odds ratio = 18.0, 95% confidence interval 3.2-100.9, P < .001 vs women, odds ratio = 3.33, 95% confidence interval 1.4-7.4, P = .003). CONCLUSIONS: Our data suggest that hyperleptinemia was a significant risk factor for HBP elderly individuals, mainly in men.

Lipoprotein(a) and cardiovascular risk factors in a cohort of 6-year-old children. The Rivas-Vaciamadrid Study.

UNLABELLED: We have studied the distribution of lipoprotein(a) (Lp(a)) and its relation to lipid profiles and a family history of cardiovascular disease in grandparents in a cohort of 673 6-year-old Spanish children. Lp(a) levels were highly skewed, showed no differences between sexes and had no relevant relations with anthropometric variables. When compared with children without a family history of stroke, children with a family history of this disorder showed significantly higher levels of Lp(a) (median 13 mg/dl, range 2-110 mg/dl versus 9 mg/dl, range 2-120 mg/dl, P=0.02). Also the percentage of children with a family history of stroke was higher in the group of children with Lp(a) levels above 30 mg/dl than in the group who exhibited lower levels (20.9% versus 10.4%, P=0.002). Children with a family history of coronary heart disease had higher levels of Lp(a) than children without such history (median 14 mg/dl, range 2-120 mg/dl versus 8 mg/dl, range 2-62 mg/dl, P=0.03). Finally, when compared with children with Lp(a) levels <30 mg/dl, those with Lp(a) levels above 30 mg/dl showed significantly higher mean levels of total cholesterol (174.9 versus 169.4 mg/dl, P<0.05), low-density lipoprotein-cholesterol (109.1 versus 102.4 mg/dl, P<0.05), and apolipoprotein B (81.9 versus 74.6 mg/dl, P<0.05). CONCLUSION: Our study shows the existence of an association between high levels of lipoprotein (a) in 6 year-old children and a family history of both cerebrovascular and coronary disease in grandparents. High levels of lipoprotein (a) were also associated with high levels of low-density lipoprotein-cholesterol and apolipoprotein B.

Hallazgos clínicos y radiológicos de vías respiratorias en una población de pacientes geriátricos / Clinical and radiologic findings of the airways in a geriatric patient population

Se realizó un estudio prospectivo de corte transversal de los pacientes internos en el Centro Geriátrico San Joaquín y Santa Ana de la ciudad de La Vega, República Dominicana, durante el período enero-marzo del 1997. Con fines de comparar diagnóstico clínico y radiológico, se investigó el total de pacientes observado en el asilo (82 pacientes), donde el 52.5// correspondieron al sexo femenino, 74.3// de los pacientes eran de bajo nivel económico. El grupo etáreo más frecuente fue el comprendido de 81-85 años. El 65.8// presentaron antecedentes de hábitos tóxicos, 35.4// con historia de enfermedad respiratoria, el 48.9// de los pacientes se hizo diagnóstico clínico de enfermedad pulmonar obstructiva crónica. (EPOC) (24.4//), de proceso gripal, (45.1//), no se hizo diagnóstico clínico de patología respiratoria. El diagnóstico radiológico más frecuente fue el de EPOC (31.8//) y en el 68.2// de los casos no se hizo diagnóstico radiológico