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Genetic polymorphisms of catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) have shown promising but inconsistent linkages with executive function (EF) in normal aging. We tested (1) independent contributions of COMT and BDNF risk; (2) potential magnification by risk-related interactions or additive effects with age; and (3) effect modification through stratification by apolipoprotein E (APOE) (risk: ε4+). Multiple linear regression models were applied with nondemented older adults (N = 634; range: 53-95 years) for an EF latent variable. No independent effects of BDNF or COMT on EF were observed. Additive (but not interactive) effects of COMT, BDNF, and age showed that older adults with a high-risk allelic combination performed differentially worse. Of 2 tested models of synergistic effects, the additive approach selectively supported a magnification hypothesis, which was qualified by the presence or the absence of APOE ε4., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We tested independent and interactive contributions of a recently noted and promising insulin degrading enzyme polymorphism (IDE; rs6583817) and type 2 diabetes (T2D) to executive function performance, concurrently and longitudinally. Regarding normal neurocognitive decline and Alzheimer's disease, T2D is a known risk factor and this IDE variant might contribute risk or risk reduction via the minor (A) or major (G) allele. We compared normal aging and T2D groups (baseline n = 574; ages 53-95 years) over 2 longitudinal waves (mean interval = 4.4 years). We used confirmatory factor analysis, latent growth curve modeling, and path analysis. A confirmed single-factor model of 4 executive function tasks established the cognitive phenotype. This IDE variant predicted concurrent group differences and differential change in cognitive performance. Furthermore, the IDE major allele reduced risk of cognitive decline. T2D predicted performance only concurrently. Both IDE and T2D are associated with executive function levels in older adults, but only IDE moderated 2-wave change. Previously linked to Alzheimer's disease, this IDE variant should be further explored for its potential influence on cognitive phenotypes of normal aging., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor participates in the trafficking of lysosomal enzymes from the trans-Golgi network or the cell surface to lysosomes. In Alzheimer's disease (AD) brains, marked up-regulation of the lysosomal system in vulnerable neuronal populations has been correlated with altered metabolic functions. To establish whether IGF-II/M6P receptors and lysosomal enzymes are altered in the brain of transgenic mice harboring different familial AD mutations, we measured the levels and distribution of the receptor and lysosomal enzymes cathepsins B and D in select brain regions of transgenic mice overexpressing either mutant presenilin 1 (PS1; PS1(M146L+L286V)), amyloid precursor protein (APP; APP(KM670/671NL+V717F)) or APP+PS1 (APP(KM670/671NL+V717F)+PS1(M146L+L286V)) transgenes. Our results revealed that levels and expression of the IGF-II/M6P receptor and lysosomal enzymes are increased in the hippocampus and frontal cortex of APP and APP+PS1, but not in PS1, transgenic mouse brains compared with wild-type controls. The changes were more prominent in APP+PS1 than in APP single transgenic mice. Additionally, all beta-amyloid-containing neuritic plaques in the hippocampal and cortical regions of APP and APP+PS1 transgenic mice were immunopositive for both lysosomal enzymes, whereas only a subset of the plaques displayed IGF-II/M6P receptor immunoreactivity. These results suggest that up-regulation of the IGF-II/M6P receptor and lysosomal enzymes in neurons located in vulnerable regions reflects an altered functioning of the endosomal-lysosomal system which may be associated with the increased intracellular and/or extracellular A beta deposits observed in APP and APP+PS1 transgenic mouse brains.

Prion protein (PrP) has been localized to amyloid-beta (Abeta) senile plaques in aging and Alzheimer disease, but it is unknown whether PrP is directly involved in plaque formation or represents a reaction to amyloid deposition. To evaluate possible functional effects of PrP in Abeta plaque formation, we analyzed bigenic mice (TgCRND8/Tg7), carrying mutant human amyloid precursor protein (APP) 695 (APP(Swed+Ind), TgCRND8) as well as the wild-type Syrian hamster prion protein gene (sHaPrP, Tg7), showing Abeta plaques at 3 months of age as well as highly increased HaPrP(c) levels. Compared to the control group, consisting of animals carrying only mutant APP, bigenic mice showed a higher number of senile plaques in the cerebral cortex, while APP transcription and Abeta40/Abeta42 levels were unchanged. Double-labelling immunofluorescence showed co-localization of Abeta and PrP in virtually all plaques in the brains of both control and experimental animals. Our data suggest that PrP promotes plaque formation, and that this hitherto unknown functional role of PrP appears to be mediated by increased Abeta aggregation rather than by altered APP transcription or processing.

Cognition in transgenic mouse models of Alzheimer's disease (AD) has been predominantly characterized in explicit spatial orientation tasks. However, dementia in AD encompasses also implicit memory systems. In the present study a line of transgenic mice (TgCRND8) encoding a double mutated allele of the human amyloid precursor protein (APP) genes was evaluated in an implicit associative learning task of conditioned taste aversion (CTA). CTA is a form of Pavlovian classical conditioning, in which a mouse learns to avoid a novel taste of saccharine (conditioned stimulus) paired with an experimentally induced (systemic injection of lithium chloride) nausea (unconditioned stimulus). In contrast to conditioned non-Tg mice, TgCRND8 APP mice developed weaker aversion against saccharine and quickly increased its consumption in repeated tests. These results indicate that TgCRND8 mice show a significant impairment not only in explicit spatial memory, as has been previously shown [Nature 408 (2000) 979], but also in implicit memory. Control experiments confirmed that TgCRND8 and non-Tg mice had comparable taste sensitivities in response to appetitive as well as aversive tastes. The study suggests that the CTA paradigm can be a sensitive tool to evaluate deficits in implicit associative learning in APP transgenic mouse models of AD.

Presenilin 1-null mice die at birth from brain and skeletal developmental deformities due to disrupted Notch signaling. Presenilin 1-null mice also have severely reduced gamma-secretase cleavage of betaAPP. The assumption has been that facilitation of Notch signaling and betaAPP processing by presenilin 1 are analogous functions. Here we describe a presenilin 1-targetted mouse model that expresses extremely low levels ( approximately 1% of normal) of mutant PS1-M146L. Homozygous mice have significantly reduced viability due to a Notch-like phenotype. The animals that survive have severe axial skeletal deformities and markedly diminished gamma-secretase activity and accumulation of betaAPP-C100, but no obvious abnormalities in brain development. These results suggest that, in mice, a marked reduction of PS1-facilitated gamma-secretase activity is not detrimental to normal brain development.

Both in vivo and in vitro investigations point to an important role for the immune system in the development of age-related neurodegeneration. Microglia isolated from aged female F344 rats, 18-20 months, show a higher percentage of cells with an ameboid morphology indicative of activation, whereas, astrocytes had a quiescent morphology. The ability of astrocytes and microglia to attenuate toxin-induced neuronal injury was examined. Post-natal day 1-3 pup cells optimally rescued neurons from Abeta-induced toxicity, whereas mixed glial cells from 18-20 month old rats were unable to rescue neurons from Abeta-induced toxicity. Our results suggested the appearance of a neurotoxic co-factor, therefore we investigated the basal level of nitric oxide and pro-inflammatory cytokines to determine if altered levels of immune mediators play a role in the toxicity. Mitogen-stimulated nitric oxide production increased 10 fold with age of donor, whereas, only the pup cells expressed an increase in TNF-alpha production. Basal levels of pro-inflammatory cytokines, as measured by RNA protection assays, increased with age. In particular, IL-1beta was increased 2 fold between adult and aged glial cells. The elevated cytokine expression may contribute to enhanced susceptibility to neurodegenerative diseases.

Dominant mutations in the Presenilin 1 gene are linked to an aggressive, early-onset form of familial Alzheimer's Disease (FAD). Spatial memory of transgenic (Tg) mice expressing either mutant (lines Tg(M146L)1, Tg(M146L)76, Tg(L286V)198) or wild type (line Tg(PS1wt)195) human PS1 transgenes was investigated in the Morris water maze (WM) test at 6 and 9 months of age. The results showed that the mutated Tg mice had increased swim speed when compared to non-Tg littermates or Tg PS1 wild type mice. The swim speed difference did not, however, significantly affect the spatial learning in the WM test and all groups showed comparable search paths during training and similar spatial bias during probe trials. When re-tested at 9 months, all mice showed significantly improved learning acquisition of spatial information. The lack of progressive spatial learning impairment in mice expressing the mutated human PS1 transgene in the WM does not preclude impairments in other cognitive tasks but suggests that full phenotypic expression of mutant PS1 alleles may require co-expression of human versions of other AD-associated genes.