Alzheimer's disease is the most common neurodegenerative disease in the elderly. Senile plaques and nerve cells in the fiber entanglement [neurofibrillary tangle (NFT)] are the significant pathological features. Currently, clinical drugs cannot effectively treat AD and reverse its pathogenesis. Therefore, it is of great importance to research and development of new AD therapy drugs. Carbazole-based cyanine is a type of synthetic small molecule compound that shares a common base with different functional groups; for example, SLOH, SLM, and SLCOOH. They exhibited selective binding to Aβ peptides and showed strong inhibition of Aβ peptide aggregation. It was found that one of the cyanines, SLOH, could significantly improve the cognitive ability of 3× Tg-AD mice treated for 40 days from the age of 4 months. In vivo, SLOH reduced Aβ levels and decreased hyperphosphorylation of tau both in the hippocampus and cortex by downregulating the activity of Akt/GSK3β and protein phosphatase 2A, SLOH can also activate the calcium pathway through activating CAMKII and cAMP-response element-binding (CREB). SLM significantly improved cognitive deficits in AD mice both in AD mice aged 4 months and 8 months. Both oligomeric Aβ and phosphorylated tau were decreased, and this was due to the activation of autophagic flux. The other cyanine compound SLCOOH also exhibited significant improvement in the cognitive ability of 4-month 3× Tg-AD mice after two months of treatment. There was significantly reduced Aβ deposition, decreased total tau, and reduced tau hyperphosphorylation by inhibiting the activities of glycogen synthase kinase-3β in 4-month 3× Tg-AD mice. SLCOOH treatment cleared Aβ and tau by upregulating the autophagy pathway, which inhibited the activity of mTOR/p70S6K. Moreover, SLCOOH structurally restored synapses and spines and regulated the Ca2+/CaMKII/CREB signaling pathway, leading to enhanced synaptic plasticity and cognitive ability in AD mice. Furthermore, we found SLCOOH ameliorated synaptic deficits by downregulating N-methyl-D-aspartate receptors (NMDAR), thereby modulating intercellular calcium ion (Ca2+) loading and upregulating neuronal calcium dependent signaling. Thus, our results demonstrated that these three carbazole-based cyanines mitigated cognitive decline by targeting Aβ and tau pathology in 3× Tg-AD mice. Those data strongly support that these three carbazole-based cyanines as a potent therapy for AD.

Thesis (Ph.D.)--Boston University / Although motor dysfunction in Parkinson's disease (PD) and memory deficits in Alzheimer's disease (AD) are the respective hallmark symptoms, both neurodegenerative disorders are also associated with significant disruptions in visual functioning. In PD, visuospatial function is impaired, particularly in patients with left-side onset of motor symptoms (LPD), reflecting pathology in right hemisphere brain regions, including the parietal lobe. LPD visuospatial performance is characterized by perceptual distortions, suggesting that lower-level visual processing may contribute to abnormal performance. In AD and PD, reduced contrast sensitivity and other visual difficulties have the potential to impact everyday functioning. The relation of PD visuospatial problems, and AD and PD contrast sensitivity deficits to higher-order impairments is understudied. The present experiments examined visual and visuospatial difficulties in these groups and evaluated an intervention to improve everyday visual function. Experiment I assessed performance on a line bisection task in PD. Participants included non-demented patients (10 LPD, 10 with right-side motor onset [RPD]) and 11 normal control adults (NC). Performance was related to data from measures of retinal structure (Optical Coherence Tomography) and function (Frequency Doubling Technology; FDT) across the eye. Correlations of structure and function were found for all groups. LPD showed predicted downward bisection bias in some sections of the left visual field. Expected rightward bisection bias in LPD was not consistently seen using this presentation method. For RPD, in some sectors, worse FDT sensitivity correlated with upward line bisection bias, as predicted. Experiment II investigated if performance of a complex, familiar visual search task (bingo) could be enhanced in AD and PD by manipulating the visual components of contrast, size, and visual complexity of task stimuli. Participants were 19 younger adults, 14 AD, 17 PD, and 33 NC. Increased stimulus size and decreased complexity improved performance for all groups. Increasing contrast also benefited the AD patients, presumably by compensating for their contrast sensitivity deficit, which was more severe than in the PD and NC groups. The general finding of improved performance across healthy and afflicted groups suggests the value of visual support as an easy-to-apply intervention to enhance cognitive performance.

No description available.

Alzheimer’s disease is a progressive neurodegenerative disorder leading to dementia. Interestingly, AD is more prevalent in women than men, where two third of the diagnosed AD population is female. The underlying neuropathology is characterized by extracellular A𝛽 plaques and intracellular tau tangles leading to neuronal cell death. The hippocampus, the main site for learning and memory exhibits the most significant neuronal loss in AD. It is also one of the primary neurogenic niches in the adult brain. A decline of hippocampal neural stem cells is a common feature of AD indicating a defect in neurogenesis. To model AD neuropathology, a triple transgenic model of AD (3xTg) was used. We hypothesize that the defects associated with adult neurogenesis precede the onset of AD hallmarks. Our data showed that neurogenesis defects are present as early as post-natal day 5 of age in the 3xTg model of AD, well before the development of the neuropathology. The early defects were also observed in the TgCRND8 model of AD at 3 months of age. Moreover, no statistically significant difference was detected between male and female mice at 3 months and 9 months of age when investigating NSC populations. This could indicate that sex may not need to be taken in consideration in research design when investigating NSC decline in 3xTg mice. These findings are of clinical relevance, as they may identify early changes that may open opportunities for therapeutic interventions aiming at preventing or delaying neurodegeneration.

Alzheimer’s disease (AD) is a neurodegenerative disease classified pathologically by the presence of tau tangles and amyloid plaques. The largest genetic risk factor for AD is the APOE ε4 allele, while the APOE ε2 allele has been linked to a protective effect for AD. Recent studies demonstrated that APOE genotypes are linked to unique omics signatures and pathological features relating to AD, such as blood-brain barrier breakage. To investigate the role of APOE genotype in AD, I analyzed different levels of omic data in blood and brain. I analyzed transcriptomic data derived from autopsied brains using network and differential gene expression approaches to identify genes and pathways involved in the APOE ε2 protective mechanism for AD. Additionally, I identified APOE genotype-specific pathways and networks involved in both blood and brain function in AD using blood and brain tissue gene expression from mostly the same individuals. Lastly, I analyzed the association of methylation of DNA from blood and brain samples with AD to identify APOE and AD specific methylation signatures and potential drug targets. Collectively, this thesis emphasizes the utility of investigating APOE genotypes individually to identify novel pathways and potential drug targets within AD subpopulations.

TREM2 is an innate immune receptor expressed in microglia and macrophages. ApoE isoforms (E2/E3/E4) are ligands of TREM2. TREM2 variants and ApoE4 are top risk factors of Alzheimer’s disease. TREM2 can be cleaved from cell membrane as soluble TREM2 (sTREM2), the level of which fluctuates during Alzheimer’s progression. However, the mechanisms that sTREM2 and the interactions between TREM2 and ApoE may contribute to Alzheimer’s neuroinflammation are largely uncharacterized. The project objectives were to investigate whether sTREM2 and ApoE isoforms can affect cytokine expression profiles in myeloid-derived cell models. My results show that sTREM2 can stimulate inflammatory cytokine expression at early time-point but anti-inflammatory cytokine expression at later time-point mainly via MAPK-JNK signaling pathway. sTREM2 has differential effects on cytokine expression in M0, M1, and M2 macrophages. ApoE isoforms also differentially induce cytokine expression and regulate TREM2 expression in M0, M1, and M2 macrophages. My study reveals a complex interplay of sTREM2, TREM2 and ApoE isoforms and differential effects of those in the models.

An environment strongly influences the behavior of individuals with dementia. A well designed physical environment can maintain and enhance the ability to function and improve quality of life. My thesis uses a residential environment for people suffering from dementia as the basis for therapeutic intervention. Understanding the physical and psychological effects of architecture on a person with dementia is an important tool in slowing the progression and effects of the disease. The competence of an individual can effect how he or she experiences a space and can make them respond more intensively to the immediate environment. Building orientation, color, lighting, and access to nature can affect the psyche of a resident and can help stabilize and reduce the effects of the disease. / Master of Architecture

Alzheimer’s Disease is a particularly vicious illness, with currently no preventative or curative treatment available. This paper focuses on how impairments in glucose metabolism and insulin signaling contribute to the disease process and further, on potential treatment options that target these specific dysfunctional processes in hopes of finding an effective cure or prevention therapy. Glucose hypometabolism presents years prior to the clinical symptoms of Alzheimer’s Disease and promotes the accumulation of Aβ, oxidative stress, and mitochondrial dysfunction. Additionally, a downregulation of GLUTs, particularly GLUT1 and GLUT3 also serves to decrease neural glucose uptake as well as to escalate glucose hypometabolism. Moreover, insulin resistance promotes tau hyperphosphorylation and extracellular aggregation of Aβ42, contributing to the Alzheimer’s Disease pathology. Due to the central role of insulin and glucose neural dysfunction to Alzheimer’s Disease, these processes pose as strong potential targets for much needed Alzheimer’s Disease curative and preventative therapy. Specifically, antioxidants and antidiabetics such as Metformin, thiazolidinediones, sulfonylureas, incretins, and intranasal insulin have shown some potential as future treatment options for Alzheimer’s Disease but require further investigation. Some non-pharmacological approaches, such as the ketogenic diet, have also been proposed as viable treatment options and work via their effects on glucose and insulin pathways. Dysfunctional glucose metabolism and insulin resistance are incredibly important in the progression of the Alzheimer’s Disease stages and as such, present as viable potential targets of future drug therapies.

Thesis (M.A.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Studies have revealed an association between periodontal disease and a number of systemic diseases, including atherosclerosis and diabetes. These findings may help physicians identify correctable causes of disease early in the course of progression or prevent disease onset entirely. As the number of possible systemic diseases associated with oral infection is being explored and expanded, cognitive impairment associated with dementia has been added to the list as a possible end organ target. This paper examines the available research focused on exploring this potential link between Alzheimer's disease and periodontal disease. Alzheimer's disease and periodontal disease are both major public health concerns that most commonly affect the elderly population. Recently, several cross-sectional studies have investigated the oral health status of individuals with Alzheimer's disease, finding that often these individuals are not able to take care of their own oral needs. This has alerted healthcare professionals and caretakers to the need for more focused attention to oral health in this population. Conversely, a small number of studies have also set out to investigate the role of pre-existing poor oral health in the development of Alzheimer's disease. The mechanisms and evidence recently published on this possible bi-directional link are reviewed in this paper. The central focus is on the role of inflammation in the central nervous system of patients with Alzheimer's disease. It is believed that chronic diseases, such as periodontal disease, can cause systemic inflammation by directly introducing bacterial pathogens, toxins, and other inflammation inducing substances into the bloodstream. Some of these studies have used detection methods to determine the presence of oral pathogens in distant body parts, including the brain. Several bacteria identified in these sites are major periodontal pathogens, which have also been linked to other systemic diseases such as atherosclerosis. Other studies have focused their research on the detection of inflammatory markers and endotoxins associated with pathogens involved in oral infection. Some studies have also indicated a significant correlation between lifetime tooth loss and impaired cognition later in life. Future research must continue to examine how periodontal pathogens and inflammation contribute to the pathology in AD, and whether the two diseases merely share common risk factors or are interrelated. Potential confounders including viral infections, head injury, low socioeconomic status, malnutrition and genetic inflammatory susceptibility must also be controlled for ill order for the results to be more conclusive While there is evidence indicating that a bidirectional link may exist between AD and periodontal disease, at this point there is still not enough evidence to establish this conclusively. Still, the studies presented here do serve as an important foundation for future research; such as randomized-controlled intervention trials with long term followup that would help elucidate causation. The results of these preliminary investigations are certainly promising enough to warrant these future studies to determine if preventative oral health measures could potentially reduce the risk of developing AD. / 2999-01-01

Proper and dignified care for an aging population, especially those with Stage IandII Alzheimer's disease is a challenge. To stay and live in one place as conditions progress irreversibly is perhaps one of the areas where architecture could make a contribution. In addition to patients, the needs of caretakers and visiting family members play a role in the program for a new facility. As an architectural premise, the focus is directed toward an environment that is memorable, provides basic comfort, and instills a sense of belonging. Essentially, the proposal advocates an architecture made operational by providing spaces that enable deep archaic memories which seem to remain present in the psyche of Alzheimer's patients even in advanced stages. / Master of Architecture