Search

Altered energy metabolism has been implicated both in aging and the pathogenesis of late-onset Alzheimer’s disease (LOAD). However, it is unclear which anomalies are acquired phenotypes and which are inherent and predispose to disease. We report that neural progenitor cells and astrocytes differentiated from LOAD patient-derived induced pluripotent stem cells exhibit multiple inter-related bioenergetic alterations including: changes in energy production by mitochondrial respiration versus glycolysis, as a consequence of alterations in bioenergetic substrate processing and transfer of reducing agents, reduced levels of NAD/NADH, diminished glucose uptake and response rates to insulin (INS)/IGF-1 signaling, decreased INS receptor and glucose transporter 1 densities, and changes in the metabolic transcriptome. Our data confirm that LOAD is a “multi-hit” disorder and provide evidence for innate inefficient cellular energy management in LOAD that likely predisposes to neurodegenerative disease with age. These processes may guide the development and testing of diagnostic procedures or therapeutic agents.

The redox co-factor nicotinamide adenine dinucleotide (NAD) declines with age, and NAD deficits are specifically associated with dysfunctional energy metabolism in late-onset Alzheimer's disease (LOAD). Nicotinamide riboside (NR), a dietary NAD precursor, has been suggested to ameliorate the aging process or neurodegeneration. We assessed whether NR with or without caffeine, which increases nicotinamide mononucleotide transferase subtype 2 (NMNAT2), an essential enzyme in NAD production, modulates bioenergetic functions in LOAD. In LOAD patients-and young or old control individuals-derived dermal fibroblasts as well as in induced pluripotent stem cell-differentiated neural progenitors and astrocytes, NR and caffeine cell type-specifically increased the NAD pool, transiently enhanced mitochondrial respiration or glycolysis and altered the expression of genes in the NAD synthesis or consumption pathways. However, continued treatment led to reversed bioenergetic effects. Importantly, NR and caffeine did not alter the characteristics of a previously documented inherent LOAD-associated bioenergetic phenotype. Thus, although NR and caffeine can partially restore diminished NAD availability, increasing NAD alone may not be sufficient to boost or restore energy metabolism in brain aging or alter aberrant energy management in LOAD. Nicotinamide riboside might still be of value in combination with other agents in preventive or therapeutic intervention strategies to address the aging process or age-associated dementia.

To compare the bone tissue response to surface-modified zirconia (ZrO2 ) and titanium implants.Cylindrical low-pressure injection moulded zirconia (ZrO2 ) implants were produced with an acid-etched surface. Titanium implants with identical shape, sandblasted and acid-etched surface (SLA) served as controls. Eighteen adult miniature pigs received both implant types in the maxilla 6 months after extraction of the canines and incisors. The animals were euthanized after 4, 8 and 12 weeks and 16 zirconia and 18 titanium implants with the surrounding tissue were retrieved, embedded in methylmethacrylate and stained with Giemsa-Eosin. The stained sections were digitized and histomorphometrically analysed with regard to peri-implant bone density (bone volume/total volume) and bone-implant contact (BIC) ratio. Statistical analysis was performed using Mann-Whitney' U-test.Histomorphometrical analysis showed direct osseous integration for both materials. ZrO2 implants revealed mean peri-implant bone density values of 60.4% (SD ± 9.9) at 4 weeks, 65.4% (SD ± 13.8) at 8 weeks, and 63.3% (SD ± 21.5) at 12 weeks after implantation, whereas Ti-SLA implants demonstrated mean values of 61.1% (SD ± 6.2), 63.6% (SD ± 6.8) and 68.2% (SD ± 5.8) at corresponding time intervals. Concerning the BIC ratio, the mean values for ZrO(2) ranged between 67.1% (SD ± 21.1) and 70% (SD ± 14.5) and for Ti-SLA between 64.7% (SD ± 9.4) and 83.7% (SD ± 10.3). For the two parameters investigated, no significant differences between both types of implants could be detected at any time point.The results indicate that there was no difference in osseointegration between ZrO2 implants and Ti-SLA controls regarding peri-implant bone density and BIC ratio.