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Most age-associated neurodegenerative disorders involve the aggregation of specific proteins within the nervous system, as occurs in Alzheimer’s disease (AD). Recent evidence indicates that Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion-like process of template protein corruption or seeding. In fact, studies in FAD-based animal models show that Aβ deposition and cerebral amyloid angiopathy may be induced by intracerebral infusion of brain extracts from AD patients or from aged APP-transgenic mice. These studies have shown that the characteristic of both the seeding agent and the host influence the pathologic signature of the Aβ seeds. In this regard, the majority of the Aβ-seeding studies have been done in APP-transgenic animal models that overproduce APP and/or Aβ. However, it remains to be elucidated whether Aβ deposition can be induced by Aβ seeds in an animal model that does not overexpress APP and produces wild type human Aβ and if these aggregates are similar to the human condition. Here, we used an innovative animal model to better understand the amyloidogenic events that occur in the sporadic form of the disease. Our model, termed hAβ-KI, expresses wild-type human Aβ under the control of the endogenous mouse APP gene. Thus, amyloid seeds from AD patients (stage C for amyloid) from the Alzheimer’s Disease Research Center (ADRC) at UCI were administered into 7-8-month-old hAβ-KI and as positive controls 3xTg-AD mice were employed. Our findings demonstrated that amyloid seeds differentially occur in 3xTg-AD and hAb-KI mice and these aggregates are developed earlier in the familial model, 3xTg-AD mice. These results suggest that multiple factors such as the seed, recipient model and time are critical factors that can modulate the amyloid pathology onset and progression. Thus, more profound understanding these factors will provide key insight on how amyloid pathology progress in AD. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech.

PURPOSE: To evaluate the role of PPARγ in regulating meibocyte differentiation and lipid synthesis in a human meibomian gland epithelial cell line (hMGEC). METHODS: HMGEC were exposed to the PPARγ agonist, Rosiglitazone, from 10–50 μM. Cultures were also exposed to specific PPARγ antagonist, T0070907, to block PPARγ receptor signaling. Cells were then stained with Ki-67 and LipidTox to determine the effects on cell cycling and lipid synthesis, respectively. Expression of meibocyte differentiation related proteins, ADFP, PPARγ, ELOVL4, and FABP4, were evaluated by quantitative PCR and western blotting. A human corneal epithelial cell line (hTCEpi) was used as a control. RESULT: Rosiglitazone significantly decreased Ki-67 staining within 2 days in a dose-dependent manner (P = 0.003) and increased lipid accumulation in hMGEC in a dose dependent manner. T0070907 suppressed both lipid droplet synthesis and cell cycle exit. Rosiglitazone significantly upregulated expression of ADFP, PPARγ, ELOVL4, and FABP4 by 9.6, 2.7, 2.6, and 3.3 fold on average (all P < 0.05 except for FABP4, P = 0.057) in hMGEC. T0070907 significantly abrogated rosiglitazone-induced upregulation of these genes when treated prior to rosiglitazone treatment (all P < 0.05). The observed lipogenic differentiation response was not duplicated in hTCEpi after exposure to rosiglitazone. CONCLUSION: Rosiglitazone induced cell cycle exit and upregulation of lipogenic gene expression leading to lipid accumulation in hMGEC. These effects were suppressed by PPARγ antagonist indicating that PPARγ signaling specifically directs lipogenesis in hMGEC. These findings suggest that PPARγ plays a critical role in meibocyte differentiation.

The majority of Alzheimer’s disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aβ under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aβ sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aβ sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAβ expression, rescues cognition and reduces the formation of PAS granules., Most instances of Alzheimer’s disease (AD) are sporadic or not associated with a particular mutation. Here, the authors develop knock-in mice that express wildtype human Aβ under control of the mouse App locus, which may have potential for modelling some aspects of sporadic late onset AD.