Kristyn A. Bates

Induction of Toll-Like Receptor 9 Signaling as a Method for Ameliorating Alzheimer's Disease-Related Pathology

The pathogenesis of Alzheimers disease (AD) is thought to be related to the accumulation of amyloid β (Aβ) in amyloid deposits and toxic oligomeric species. Immunomodulation is emerging as an effective means of shifting the equilibrium from Aβ accumulation to clearance; however, excessive cell mediated inflammation and cerebral microhemorrhages are two forms of toxicity which can occur with this approach. Vaccination studies have so far mainly targeted the adaptive immune system. In the present study, we have stimulated the innate immune system via the Toll-like receptor 9 (TLR9) with cytosine-guanosine-containing DNA oligodeoxynucleotides in Tg2576 AD model transgenic mice. This treatment produced a 66% and 80% reduction in the cortical (p = 0.0001) and vascular (p = 0.0039) amyloid burden, respectively, compared with nontreated AD mice. This was in association with significant reductions in Aβ42, Aβ40, and Aβ oligomer levels. We also show that treated Tg mice performed similarly to wild-type mice on a radial arm maze. Our data suggest that stimulation of innate immunity via TLR9 is highly effective at reducing the parenchymal and vascular amyloid burden, along with Aβ oligomers, without apparent toxicity.

Bone mineral density, adiposity, and cognitive functions

Cognitive decline and dementia due to Alzheimers disease (AD) have been associated with genetic, lifestyle, and environmental factors. A number of potentially modifiable risk factors should be taken into account when preventive or ameliorative interventions targeting dementia and its preclinical stages are investigated. Bone mineral density (BMD) and body composition are two such potentially modifiable risk factors, and their association with cognitive decline was investigated in this study. 164 participants, aged 34–87 years old (62.78 ± 9.27), were recruited for this longitudinal study and underwent cognitive and clinical examinations at baseline and after 3 years. Blood samples were collected for apolipoprotein E (APOE) genotyping and dual energy x-ray absorptiometry (DXA) was conducted at the same day as cognitive assessment. Using hierarchical regression analysis, we found that BMD and lean body mass, as measured using DXA were significant predictors of episodic memory. Age, gender, APOE status, and premorbid IQ were controlled for. Specifically, the List A learning from California Verbal Learning Test was significantly associated with BMD and lean mass both at baseline and at follow up assessment. Our findings indicate that there is a significant association between BMD and lean body mass and episodic verbal learning. While the involvement of modifiable lifestyle factors in human cognitive function has been examined in different studies, there is a need for further research to understand the potential underlying mechanisms.

Olfactory discrimination predicts cognitive decline among community-dwelling older adults

The presence of olfactory dysfunction in individuals at higher risk of Alzheimers disease has significant diagnostic and screening implications for preventive and ameliorative drug trials. Olfactory threshold, discrimination and identification can be reliably recorded in the early stages of neurodegenerative diseases. The current study has examined the ability of various olfactory functions in predicting cognitive decline in a community-dwelling sample. A group of 308 participants, aged 46–86 years old, were recruited for this study. After 3 years of follow-up, participants were divided into cognitively declined and non-declined groups based on their performance on a neuropsychological battery. Assessment of olfactory functions using the Sniffin’ Sticks battery indicated that, contrary to previous findings, olfactory discrimination, but not olfactory identification, significantly predicted subsequent cognitive decline (odds ratio=0.869; P<0.05; 95% confidence interval=0.764−0.988). The current study findings confirm previously reported associations between olfactory and cognitive functions, and indicate that impairment in olfactory discrimination can predict future cognitive decline. These findings further our current understanding of the association between cognition and olfaction, and support olfactory assessment in screening those at higher risk of dementia.

Chronic gliosis triggers Alzheimer's disease-like processing of amyloid precursor protein

Alzheimers disease is a progressively dementing illness characterized by the extracellular accumulation and deposition of beta-amyloid. Early onset Alzheimers disease is linked to mutations in three genes, all of which lead to increased beta-amyloid production. Inflammatory changes and gliosis may also play a role in the disease process, but the importance of these reactive events remains unclear. We recently reported that chronic cortical gliosis in heterotopic fetal rat cortical transplants is associated with significant changes in the levels of some of the proteins implicated in the pathogenesis of Alzheimers disease. Because rodent beta-amyloid does not form extracellular amyloid deposits, we have now extended this model of chronic cortical gliosis to transgenic mice expressing the Swedish mutant form of human amyloid precursor protein. In addition, apolipoprotein E knockout mice were used to elucidate the role of this protein in reactive gliosis. The expression of mutant and murine proteins was assayed 6 or 10 months after transplantation using immunohistochemical and western blot methods. Heterotopic transplantation of fetal cortex onto the midbrain of neonatal mice consistently resulted in reactive gliosis, independent of apolipoprotein E status. In contrast, in homotopic cortex-to-cortex grafts there was little alteration in glial reactivity, a result similar to that obtained previously in rats. By 10 months post-transplantation the level of presenilin-1 expression was lower in heterotopic grafts than in host cortex and there was increased expression of transgenic amyloid precursor protein, but only in the gliotic cortex-to-midbrain grafts. Most importantly, increased levels of beta-amyloid, and particularly its precursor, C-99, were selectively found in these heterotopic transplants. Our results show that chronic gliosis is associated with altered processing of the amyloid precursor protein in vivo and thus may initiate or exacerbate pathological changes associated with Alzheimers disease.

Latrepirdine: Molecular mechanisms underlying potential therapeutic roles in Alzheimer’s and other neurodegenerative diseases

Latrepirdine (DimebonTM) was originally marketed as a non-selective antihistamine in Russia. It was repurposed as an effective treatment for patients suffering from Alzheimer’s disease (AD) and Huntington’s disease (HD) following preliminary reports showing its neuroprotective functions and ability to enhance cognition in AD and HD models. However, latrepirdine failed to show efficacy in phase III trials in AD and HD patients following encouraging phase II trials. The failure of latrepirdine in the clinical trials has highlighted the importance of understanding the precise mechanism underlying its cognitive benefits in neurodegenerative diseases before clinical evaluation. Latrepirdine has shown to affect a number of cellular functions including multireceptor activity, mitochondrial function, calcium influx and intracellular catabolic pathways; however, it is unclear how these properties contribute to its clinical benefits. Here, we review the studies investigating latrepirdine in cellular and animal models to provide a complete evaluation of its mechanisms of action in the central nervous system. In addition, we review recent studies that demonstrate neuroprotective functions for latrepirdine-related class of molecules including the β-carbolines and aminopropyl carbazoles in AD, Parkinson’s disease and amyotrophic lateral sclerosis models. Assessment of their neuroprotective effects and underlying biological functions presents obvious value for developing structural analogues of latrepirdine for dementia treatment.

Altered Expression of Apolipoprotein E, Amyloid Precursor Protein and Presenilin-1 is associated with chronic reactive gliosis in rat cortical tissue

A major characteristic feature of Alzheimers disease is the formation of compact, extracellular deposits of beta-amyloid (senile plaques). These deposits are surrounded by reactive astrocytes, microglia and dystrophic neurites. Mutations in three genes have been implicated in early-onset familial Alzheimers disease. However, inflammatory changes and astrogliosis are also believed to play a role in Alzheimers pathology. What is unclear is the extent to which these factors initiate or contribute to the disease progression. Previous rat studies demonstrated that heterotopic transplantation of foetal cortical tissue onto the midbrain of neonatal hosts resulted in sustained glial reactivity for many months. Similar changes were not seen in cortex-to-cortex grafts. Using this model of chronic cortical gliosis, we have now measured reactive changes in the levels of the key Alzheimers disease proteins, namely the amyloid precursor protein, apolipoprotein E and presenilin-1. These changes were visualised immunohistochemically and were quantified by western blot analysis. We report here that chronic cortical gliosis in the rat results in a sustained increase in the levels of apolipoprotein E and total amyloid precursor protein. Reactive astrocytes in heterotopic cortical grafts were immunopositive for both of these proteins. Using a panel of amyloid precursor protein antibodies we demonstrate that chronic reactive gliosis is associated with alternative cleavage of the peptide. No significant changes in apolipoprotein E or amyloid precursor protein expression were seen in non-gliotic cortex-to-cortex transplants. Compared to host cortex, the levels of both N-terminal and C-terminal fragments of presenilin-1 were significantly lower in gliotic heterotopic grafts.The changes described here largely mirror those seen in the cerebral cortex of humans with Alzheimers disease and are consistent with the proposal that astrogliosis may be an important factor in the pathogenesis of this disease.

Fluoro-2-Deoxy-D-Glucose (FDG)-PET in APOEε4 Carriers in the Australian Population

Apolipoprotein E-epsilon4 (APOEepsilon4) has been associated with increased risk of developing Alzheimers disease (AD) and regional cerebral glucose hypometabolism, as measured by fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET). We report here preliminary data from studies that aim to determine whether cerebral glucose hypometabolism is observed in APOEepsilon4 positive, cognitively intact individuals between the ages of 50 and 80, and whether there is an additional impact of subjective memory complainer (SMC) status on glucose metabolism determined by NeuroStat analysis. FDG-PET was conducted in 30 community dwelling, APOE-epsilon4 carriers without clinical evidence of dementia and objective cognitive impairment as assessed using a neuropsychological battery. Neurological soft-signs (NSS) were also assessed. Glucose hypometabolism was demonstrated in the anterior and posterior cingulate cortex and in the temporal association cortices in APOEepsilon4 carriers compared to the normative NeuroStat database. This pattern was particularly evident in APOEepsilon4 heterozygous individuals. SMC showed hypometabolism in the aforementioned brain regions, whereas non-SMC showed no significant pattern of glucose hypometabolism. FDG-PET with NeuroStat analysis showed that APOEepsilon4 carriers have mild glucose hypometabolism in areas associated with AD. SMC may be associated with AD-related differences in regional cerebral glucose metabolism. These findings are currently being investigated in a larger group of APOEepsilon4 carriers.

Protein markers for Alzheimer disease in the frontal cortex and cerebellum

Objective: To compare proteins related to Alzheimer disease (AD) in the frontal cortex and cerebellum of subjects with early-onset AD (EOAD) with or without presenilin 1 (PS1) mutations with sporadic late-onset AD (LOAD) and nondemented control subjects. Methods: Immunohistochemistry, immunoblot analysis, and ELISA were used to detect and assess protein levels in brain. Results: In EOAD and to a lesser extent in LOAD, there was increased amyloid beta (Aβ) deposition (by immunohistochemistry), increased soluble Aβ (by immunoblot analysis), and specific increases in Aβ40 and Aβ42 (by ELISA) in the frontal cortex and, in some cases, in the cerebellum. Surprisingly, immunoblot analysis revealed reduced levels of PS1 in many of the subjects with EOAD with or without PS1 mutations. In those PS1 mutation-bearing subjects with the highest Aβ, PS1 was barely, if at all, detectable. This decrease in PS1 was specific and not attributable solely to neuronal loss because amyloid precursor protein (APP) and the PS1-interacting protein β-catenin levels were unchanged. Conclusions: This study shows that in the frontal cortex and cerebellum from Alzheimer disease patients harboring certain presenilin 1 mutations, high levels of amyloid beta are associated with low levels of presenilin 1. The study provides the premise for further investigation of mechanisms underlying the downregulation of presenilin 1, which may have considerable pathogenic and therapeutic relevance.

Association of Cardiovascular Factors and Alzheimer's Disease Plasma Amyloid-β Protein in Subjective Memory Complainers

A strong link is indicated between cardiovascular disease (CVD) and risk for developing Alzheimers disease (AD), which may be exacerbated by the major AD genetic risk factor apolipoprotein Eepsilon4 (APOEepsilon4). Since subjective memory complaint (SMC) may potentially be an early indicator for cognitive decline, we examined CVD risk factors in a cohort of SMC. As amyloid-beta (Abeta) is considered to play a central role in AD, we hypothesized that the CVD risk profile (increased LDL, reduced HDL, and increased body fat) would be associated with plasma Abeta levels. We explored this in 198 individuals with and without SMC (average age = 63 years). Correlations between Abeta40 and HDL were observed, which were stronger in non-APOEepsilon4 carriers (rho = -0.315, p < 0.001) and in SMC (rho = -0.322, p = 0.01). There was no relationship between percentage body fat and Abeta40 in this cohort. Age and HDL remained predictive for plasma Abeta40 using multivariate regression analysis. We report a novel negative association between HDL and Abeta, which if demonstrated to be causal has implications for the development of lifestyle interventions and/or novel therapeutics. The relationship between HDL and Abeta and the potential significance of such an association needs to be validated in a larger longitudinal study.

The Relationship Between Memory Complaints, Perceived Quality of Life and Mental Health in Apolipoprotein Eε4 Carriers and Non-Carriers

Apolipoprotein E epsilon4 (APOE-epsilon4) is a major genetic risk factor for Alzheimers disease. In this study, we addressed the question of whether possession of the APOE-epsilon4 allele results in adverse effects on perceived health-related quality of life (HRQL) and on symptoms of depression and anxiety in people with subjective memory complaints (SMC). 138 healthy, community-dwelling elderly volunteers, aged 52 to 85, were assessed for HRQL, depression, and anxiety. The participants were classified as i) APOE-epsilon4 carriers or ii) non-carriers with a) SMC or b) without memory complaints. The possible interactions of APOE genotype, gender, and SMC on HRQL, depression, and anxiety were investigated statistically. SMC was significantly associated with poorer outcomes on measures of depression, trait anxiety, and mental health. APOE-epsilon4 carriers did not significantly differ from non-carriers on HRQL, depression, and anxiety. However, significant interaction was found between APOE-epsilon4 genotype and SMC on depression. These findings are important from a health perspective and suggest that memory complaints are associated with markers of mental health and quality of life that are independent of possession of the APOE-epsilon4 allele, despite the importance of this polymorphism in the risk of AD and other health problems.