Alzheimer's Disease-Related Polymorphisms in Shunt-Responsive Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a late onset, surgically treated progressive brain disease caused by impaired cerebrospinal fluid dynamics and subsequent ventriculomegaly. Comorbid Alzheimer's disease (AD) seems to be frequent in iNPH. OBJECTIVE: We aim to evaluate the role of AD-related polymorphisms in iNPH. METHODS: Overall 188 shunt-operated iNPH patients and 688 controls without diagnosed neurodegenerative disease were included into analysis. Twenty-three single-nucleotide polymorphisms (SNPs FRMD4A [rs7081208_A, rs2446581_A, rs17314229_T], CR1, BIN, CD2AP, CLU, MS4A6A, MS4A4E, PICALM, ABCA7, CD33, INPP5D, HLA_DRB5, EPHA1, PTK2B, CELF1, SORL1, FERMT2, SLC24A, DSG2, CASS4, and NME8) adjusted to APOE were analyzed between groups by using binary logistic regression analysis. Neuroradiological characteristics and AD-related changes in the right frontal cortical brain biopsies were available for further analysis. RESULTS: Logistic regression analysis adjusted to age, gender, and other SNPs indicated allelic variation of NME8 between iNPH patients and non-demented controls (p = 0.014). The allelic variation of NME8 was not related to the neuropathological changes in the brain biopsies of iNPH patients. However, periventricular white matter changes (p = 0.017) were more frequent in the iNPH patients with the AA-genotype, an identified risk factor of AD. CONCLUSIONS: Our findings increase the evidence that iNPH is characterized by genetic and pathophysiological mechanisms independent from AD. Considering that NME8 plays a role in the ciliary function and displays SNP-related diversity in white matter changes, the mechanisms of NME8 in iNPH and other neurodegenerative processes are worth further study.

Effects of Alzheimer's Disease-Associated Risk Loci on Amyloid-ß Accumulation in the Brain of Idiopathic Normal Pressure Hydrocephalus Patients.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition featuring characteristic symptoms, ventriculomegaly, and normal or slightly elevated cerebrospinal fluid pressure. In Alzheimer's disease (AD) patients, diffuse aggregates of amyloid-ß (Aß) and neurofibrillary hyperphosphorylated tau are detected in the neocortex of the brain, while similar accumulation of Aß is also detected in iNPH. Recent genome-wide association studies have identified several novel risk loci for AD, potentially affecting Aß-related cellular processes. Apart from the apolipoprotein E ɛ4 allele (APOE4), the risk effect of single loci is low, emphasizing the importance of the polygenic risk score approach when assessing the combined effects. OBJECTIVE: To study the effects of AD-associated individual and polygenic risk score of single nucleotide polymorphisms (SNPs) on the accumulation of Aß in the brain samples of iNPH patients. METHODS: A sample set of frontal cortex biopsies from 188 iNPH patients were divided into two groups according to the Aß pathology. After the genotyping of the AD-associated risk loci, polygenic risk score was calculated for each iNPH patient and subsequently analyzed in relation to Aß deposition. RESULTS: Apart from the APOE4, none of the SNPs revealed a statistically significant effect on the accumulation of Aß in iNPH. Also, the non-APOE4 polygenic risk score did not associate with Aß deposition. CONCLUSION: Novel AD-associated risk genes have no significant effect on Aß accumulation in the brain of iNPH patients. However, APOE4 affects the Aß deposition in the brain of iNPH and AD patients in a similar manner.

The Expression of Transthyretin and Amyloid-ß Protein Precursor is Altered in the Brain of Idiopathic Normal Pressure Hydrocephalus Patients.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition in which Alzheimer's disease (AD)-related amyloid-ß (Aß) plaques are frequently observed in the neocortex. iNPH patients with prominent Aß pathology show AD-related alterations in amyloid-ß protein precursor (AßPP) processing resulting from increased γ-secretase activity. OBJECTIVES: Our goal was to assess potential alterations in the global gene expression profile in the brain of iNPH patients as compared to non-demented controls and to evaluate the levels of the identified targets in the cerebrospinal fluid (CSF) of iNPH patients. METHODS: The genome-wide expression profile of ~35,000 probes was assessed in the RNA samples obtained from 22 iNPH patients and eight non-demented control subjects using a microarray chip. The soluble levels of sAßPPα, sAßPPß, and transthyretin (TTR) were measured from the CSF of 102 iNPH patients using ELISA. RESULTS: After correcting the results for multiple testing, significant differences in the expression of TTR and A ßPP were observed between iNPH and control subjects. The mRNA levels of TTR were on average 17-fold lower in iNPH samples compared to control samples. Conversely, the expression level of A ßPP was on average three times higher in iNPH samples as compared to control samples. Interestingly, the expression of α-secretase (ADAM10) was also increased in iNPH patients. In the lumbar CSF samples, soluble TTR levels showed a significant positive correlation with sAßPPα and sAßPPß, but TTR levels did not predict the brain pathology or the shunt response. CONCLUSIONS: These findings suggest differences in the expression profile of key factors involved in AD-related cellular events in the brain of iNPH patients.

Serine 62-Phosphorylated MYC Associates with Nuclear Lamins and Its Regulation by CIP2A Is Essential for Regenerative Proliferation.

An understanding of the mechanisms determining MYC's transcriptional and proliferation-promoting activities in vivo could facilitate approaches for MYC targeting. However, post-translational mechanisms that control MYC function in vivo are poorly understood. Here, we demonstrate that MYC phosphorylation at serine 62 enhances MYC accumulation on Lamin A/C-associated nuclear structures and that the protein phosphatase 2A (PP2A) inhibitor protein CIP2A is required for this process. CIP2A is also critical for serum-induced MYC phosphorylation and for MYC-elicited proliferation induction in vitro. Complementary transgenic approaches and an intestinal regeneration model further demonstrated the in vivo importance of CIP2A and serine 62 phosphorylation for MYC activity upon DNA damage. However, targeting of CIP2A did not influence the normal function of intestinal crypt cells. These data underline the importance of nuclear organization in the regulation of MYC phosphorylation, leading to an in vivo demonstration of a strategy for inhibiting MYC activity without detrimental physiological effects.

Increased γ-secretase activity in idiopathic normal pressure hydrocephalus patients with ß-amyloid pathology.

The potential similarity between the brain pathology of idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer disease (AD) is intriguing and thus further studies focusing on the underlying molecular mechanisms may offer valuable information for differential diagnostics and the development of treatments for iNPH. Here, we investigated ß- and γ-secretase activities in relation to amyloid-ß (Aß) pathology in the brain tissue samples collected from iNPH and AD patients. ß- and γ-secretase activities were measured from the frontal cortical biopsies of 26 patients with suspected iNPH as well as post-mortem tissue samples from the inferior temporal cortex of 74 AD patients and eight subjects without neurofibrillary pathology. In iNPH samples with detectable Aß plaques, γ-secretase activity was significantly increased (∼ 1.6-fold) when compared to iNPH samples without Aß plaques (p = 0.009). In the AD samples, statistically significant differences in the γ-secretase activity were not observed with respect to disease severity (mild, moderate and severe AD according to neurofibrillary pathology). Conversely, ß-secretase activity was unaltered in iNPH samples with or without Aß plaques, while it was significantly increased in relation to disease severity in the AD patients. These results show for the first time increased γ-secretase but not ß-secretase activity in the biopsy samples from the frontal cortex of iNPH patients with AD-like Aß pathology. Conversely, the opposite was observed in these secretase activities in AD patients with respect to neurofibrillary pathology. Despite the resemblances in the Aß pathology, iNPH and AD patients appear to have marked differences in the cellular mechanisms responsible for the production of Aß.

Protein-mediated selective enclosure of early replicators inside of membranous vesicles: first step towards cell membranes.

Containment in cell membranes is essential for all contemporary life, and apparently even the earliest life forms had to be somehow contained. It has been postulated that random enclosure of replicating molecules inside of spontaneously assembled vesicles would have formed the initial cellular ancestors. However, completely random re-formation or division of such primitive vesicles would have abolished the heritability of their contents, nullifying any selective advantage to them. We propose that the containment of the early replicators in membranous vesicles was adopted only after the invention of genetically encoded proteins, and that selective enclosure of target molecules was mediated by specific proteins. A similar containment process is still utilised by various RNA- and retroviruses to isolate their replication complexes from the host's intracellular environment. Such selective encapsulation would have protected the replicators against competitor and parasitic sequences, and provided a strong positive selection within the replicator communities.