Brief update on different roles of tau in neurodegeneration

Both Alzheimer's disease (AD) and almost every second case of frontotemporal lobar degeneration (FTLD) are characterized by the deposition of hyperphosphorylated forms of the microtubule-associated protein tau in neurons and/or glia. This unifying pathology led to coining the umbrella term "tauopathies" for these conditions. While the deposition of tau ultimately results in the formation of typical histopathological lesions, such as the neurofibrillary tangles (NFTs) in AD, it is now well accepted that tau interferes with normal functions in neurons already before its deposition. Together with the identification of pathogenic mutations in the tau-encoding gene MAPT in FTLD and evidence from a rising number of in vivo animal models a central role of tau in neurodegeneration has emerged. Here, we review the role of pathological tau in axonal transport, mitochondrial respiration, and in mediating amyloid-β toxicity in AD. Furthermore, we review recent findings regarding the spreading of tau pathology throughout the brain as disease progresses.     

Longitudinal Study of Performance on the Ruff Figural Fluency Test in Persons Aged 35 Years or Older

The Ruff Figural Fluency Test (RFFT) is a cognitive test to measure executive function. Longitudinal studies have shown that repeated testing improves performance on the RFFT. Such a practice effect may hinder the interpretation of test results in a clinical setting. Therefore, we investigated the longitudinal performance on the RFFT in persons aged 35–82 years. Performance on the RFFT was measured three times over an average follow-up period of six years in 2,515 participants of the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study in Groningen, the Netherlands: 53% men; mean age (SD), 53 (10) years. The effect of consecutive measurements on performance on the RFFT was investigated with linear multilevel regression models that also included age, gender, educational level and the interaction term consecutive measurement number x age as independent variables. It was found that the mean (SD) number of unique designs on the RFFT increased from 73 (26) at the first measurement to 79 (27) at the second measurement and to 83 (26) at the third measurement (p<0.001). However, the increase per consecutive measurement number was negatively associated with age and decreased with 0.23 per one-year increment of age (p<0.001). The increase per consecutive measurement number was not dependent on educational level. Similar results were found for the median (IQR) number of perseverative errors which showed a small but statistically significant increase with repeating testing: 7 (3–13) at the first measurement, 7 (4–14) at the second measurement and 8 (4–15) at the third measurement (p _trend = 0.002). In conclusion, the performance on the RFFT improved by repeating the test over an average follow-up period of three to six years. This practice effect was the largest in young adults and not dependent on educational level.     

The Interaction of Age and Type 2 Diabetes on Executive Function and Memory in Persons Aged 35 Years or Older

It is generally assumed that type 2 diabetes increases the risk of cognitive dysfunction in old age. As type 2 diabetes is frequently diagnosed before the age of 50, diabetes-related cognitive dysfunction may also occur before the age of 50. Therefore, we investigated the association of type 2 diabetes with cognitive function in people aged 35–82 years. In a cross-sectional study comprising 4,135 participants of the Prevention of Renal and Vascular ENd-stage Disease study (52% men; mean age (SD), 55 (12) years) diabetes was defined according to the criteria of the American Diabetes Association. Executive function was measured with the Ruff Figural Fluency Test (RFFT; worst score, 0 points; best score, 175 points), and memory was measured with the Visual Association Test (VAT; worst score, 0 points; best score, 12 points). The association of diabetes with cognitive function was investigated with multiple linear or, if appropriate, logistic regression analysis adjusting for other cardiovascular risk factors and APOE ε4 carriership. Type 2 diabetes was ascertained in 264 individuals (6%). Persons with diabetes had lower RFFT scores than persons without diabetes: mean (SD), 51 (19) vs. 70 (26) points (p<0.001). The difference in RFFT score was largest at age 35–44 years (mean difference 32 points; 95% CI, 15 to 49; p<0.001) and gradually decreased with increasing age. The association of diabetes with RFFT score was not modified by APOE ε4 carriership. Similar results were found for VAT score as outcome measure although these results were only borderline statistically significant (p≤0.10). In conclusion, type 2 diabetes was associated with cognitive dysfunction, especially in young adults. This was independent of other cardiovascular risk factors and APOE ε4 carriership.     

Statin Use and Cognitive Function: Population-Based Observational Study with Long-Term Follow-Up

We aimed to evaluate the association between statin use and cognitive function. Cognitive function was measured with the Ruff Figural Fluency Test (RFFT; worst score, 0; best score, 175 points) and the Visual Association Test (VAT; low performance, 0–10; high performance, 11–12 points) in an observational study that included 4,095 community-dwelling participants aged 35–82 years. Data on statin use were obtained from a computerized pharmacy database. Analysis were done for the total cohort and subsamples matched on cardiovascular risk (N = 1232) or propensity score for statin use (N = 3609). We found that a total of 904 participants (10%) used a statin. Statin users were older than non-users: mean age (SD) 61 (10) vs. 52 (11) years (p<0.001). The median duration of statin use was 3.8 (interquartile range, 1.6–4.5) years. Unadjusted, statin users had worse cognitive performance than non-users. The mean RFFT score (SD) in statin users and non-users was 58 (23) and 72 (26) points, respectively (p<0.001). VAT performance was high in 261 (29%) statin users and 1351 (43%) non-users (p<0.001). However, multiple regression analysis did not show a significant association of RFFT score with statin use (B, −0.82; 95%CI, −2.77 to 1.14; p = 0.41) nor with statin solubility, statin dose or duration of statin use. Statin users with high doses or long-term use had similar cognitive performance as non-users. This was found in persons with low as well as high cardiovascular risk, and in younger as well as older subjects. Also, the mean RFFT score per quintile of propensity score for statin use was comparable for statin users and non-users. Similar results were found for the VAT score as outcome measure. In conclusion, statin use was not associated with cognitive function. This was independent of statin dose or duration of statin use.     

Cytoplasmic accumulation and aggregation of TDP-43 upon proteasome inhibition in cultured neurons

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by intraneuronal deposition of the nuclear TAR DNA-binding protein 43 (TDP-43) caused by unknown mechanisms. Here, we studied TDP-43 in primary neurons under different stress conditions and found that only proteasome inhibition by MG-132 or lactacystin could induce significant cytoplasmic accumulation of TDP-43, a histopathological hallmark in disease. This cytoplasmic accumulation was accompanied by phosphorylation, ubiquitination and aggregation of TDP-43, recapitulating major features of disease. Proteasome inhibition produced similar effects in both hippocampal and cortical neurons, as well as in immortalized motor neurons. To determine the contribution of TDP-43 to cell death, we reduced TDP-43 expression using small interfering RNA (siRNA), and found that reduced levels of TDP-43 dose-dependently rendered neurons more vulnerable to MG-132. Taken together, our data suggests a role for the proteasome in subcellular localization of TDP-43, and possibly in disease.     

Animal models reveal role for tau phosphorylation in human disease

Many proteins that are implicated in human disease are posttranslationally modified. This includes the microtubule-associated protein tau that is deposited in a hyperphosphorylated form in brains of Alzheimer's disease patients. The focus of this review article is on the physiological and pathological phosphorylation of tau; the relevance of aberrant phosphorylation for disease; the role of kinases and phosphatases in this process; its modeling in transgenic mice, flies, and worms; and implications of phosphorylation for therapeutic intervention.     

Tilapia are able to withstand long-term exposure to low environmental pH, judged by their energy status, ionic balance and plasma cortisol

Tilapia Oreochromis mossambicus were exposed to water at pH 4·0 for 37 days. The water was acidified slowly over 6 h enabling the animals to acclimate and preventing damage of the gill epithelium. Additional stressors, e.g. aluminium ions and handling stress, were avoided. No mortality or decreased food consumption was observed during the exposure period. No significant changes were observed between the control and acid exposed groups for the energy rich compounds and related parameters, i.e. the adenylate energy charge, the pool of total adenine nucleotides, and the IMP load of white muscle and liver, indicating maintenance of homeostasis. Moreover, there were no significant differences between control groups and acidified groups at 3, 17 and 37 days for plasma sodium, chloride, cortisol and glucose, implying that ionic balance was maintained and that there was no activation of the pituitary-interrenal axis. It is concluded that tilapia can acclimate to water at pH 4·0 when the acidification rate is slow and additional stressors are avoided.