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Background: In Alzheimer’s disease (AD), and amyloid models such as the 5XFAD mouse, butyrylcholinesterase (BChE) is associated with β-amyloid (Aβ) plaques and has unique biochemical features which distinguish it from that found in neurons. It has been suggested that BChE associated with Aβ plaques may be involved in the maturation of this structure and thus disease progression. Objective: Currently, it is unknown whether BChE bound to Aβ plaques has altered biochemical properties due to a different primary structure or because of the association of this enzyme with Aβ plaques. Also, the source and binding mechanism of this BChE remains unknown. Methods: Brain tissue sections from the 5XFAD/BChE-KO mouse were incubated with exogenous sources of BChE and stained for this enzyme’s activity. Efforts were made to determine what region of BChE or Aβ may be involved in this association. Results: We found that incubation of 5XFAD/BChE-KO brain tissues with exogenous BChE led to this enzyme becoming associated with Aβ plaques and neurons. In contrast to neuronal BChE, the BChE bound to Aβ plaques had similar biochemical properties to those seen in AD. Mutations to BChE and efforts to block Aβ epitomes failed to prevent this association. Conclusion: The association of BChE with Aβ plaques, and the resultant biochemical changes, suggests that BChE may undergo a conformational change when bound to Aβ plaques but not neurons. The 5XFAD/BChE-KO model is ideally suited to explore the binding mechanism of BChE to Aβ plaques as well as the involvement of BChE in AD pathogenesis.

Background: Although mood and sleep disturbances are nearly universal among patients with Alzheimer's disease (AD), brain structures involved in non-cognitive processing remain under characterized in terms of AD pathology. Objectives: This study was designed to evaluate hallmarks of AD pathology in the brainstem of the APPswe/PS1dE9 mouse model of familial AD. Methods: Fresh-frozen sections from female, 12 month old, transgenic and control B6C3 mice (n=6/genotype) were examined for amyloid burden and neurofibrillary alterations, by using 6E10 immunohistochemistry and the Gallyas silver stain, respectively. Serotonin transporter (SERT) densities in the dorsal and the median raphe were quantified by [3H]DASB autoradiography. SERT mRNA expression was measured by RT-PCR and visualized by in situ hybridization. Neuroinflammation was evaluated by immunohistochemical staining for microglia and astrocytes, and by measuring mRNA levels of the proinflammatory cytokines TNF-α, IL-1β and IL-6. Results: No amyloid- and tau-associated lesions were observed in the midbrain raphe of 12 month old APPswe/PS1dE9 mice. SERT binding levels were reduced in transgenic animals compared to age-matched controls, and SERT mRNA levels were decreased by at least 50% from control values. Intense microglial, but not astrocytic immunoreactivity was observed in APPswe/PS1dE9 vs. wild-type mice. Levels of TNF-α mRNA were two-fold higher than control and correlated positively with SERT mRNA expression levels in transgenic animals. Conclusions: There was no amyloid accumulation and tau-associated pathology in the midbrain raphe of 12 month old APPswe/PS1dE9 mice. However, there was a local neuroinflammatory response with loss of serotonergic markers, which may partially account for some of the behavioral symptoms of AD.

Brain glucose hypometabolism has been observed in Alzheimer’s disease (AD) patients, and is detected with 18 F radiolabelled glucose, using positron emission tomography. A pathological hallmark of AD is deposition of brain β - amyloid plaques that may influence cerebral glucose metabolism. The five times familial AD (5XFAD) mouse is a model of brain amyloidosis exhibiting AD-like phenotypes. This study examines brain β -amyloid plaque deposition and 18 FDG uptake, to search for an early biomarker distinguishing 5XFAD from wild-type mice. Thus, brain 18 FDG uptake and plaque deposition was studied in these mice at age 2, 5 and 13 months. The 5XFAD mice demonstrated significantly reduced brain 18 FDG uptake at 13 months relative to wild-type controls but not in younger mice, despite substantial β - amyloid plaque deposition. However, by comparing the ratio of uptake values for glucose in different regions in the same brain, 5XFAD mice could be distinguished from controls at age 2 months. This method of measuring altered glucose metabolism may represent an early biomarker for the progression of amyloid deposition in the brain. We conclude that brain 18 FDG uptake can be a sensitive biomarker for early detection of abnormal metabolism in the 5XFAD mouse when alternative relative uptake values are utilized.

The serine hydrolase butyrylcholinesterase (BChE), like the related enzyme acetylcholinesterase (AChE), co-regulates metabolism of the neurotransmitter acetylcholine. In the human brain BChE is mainly expressed in white matter and glia and in distinct populations of neurons in regions that are important in cognition and behavior, functions compromised in Alzheimer's disease (AD). AD is a neurodegenerative disorder causing dementia with no cure nor means for definitive diagnosis during life. In AD, BChE is found in association with pathology, such as β-amyloid (Aβ) plaques, particularly in the cerebral cortex where BChE is not normally found in quantity. Up to 30% of cognitively normal older adults have abundant Aβ deposition in the brain. We have designed an imaging agent that can detect, through autoradiography, BChE-associated Aβ plaques in the cerebral cortex of AD brains, but does not visualize Aβ plaques in brains of cognitively normal individuals. Furthermore, in an AD mouse model with BChE gene knocked out, there are up to 70% fewer fibrillar Aβ brain plaques, suggesting diminished BChE activity could prove beneficial as a curative approach to AD. To that end, we have examined numerous N-10-carbonyl phenothiazines that are specific inhibitors of human BChE, revealing important details of the enzyme's active site gorge. These phenothiazines can be designed without potential side effects caused by neurotransmitter receptor interactions. In conclusion, BChE is potentially an important target for diagnosis and treatment of AD.

Cholinesterase activity associated with neuritic plaques (NPs) and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brains exhibit altered histochemical properties, such as requiring lower pH (6.8) for optimal cholinesterase staining compared to the pH (8.0) for best visualization of cholinesterases in neurons. Furthermore, visualization of NPs and NFTs can be prevented by agents like the peptidase inhibitor/metalloantibiotic bacitracin. The anomalous behavior of cholinesterases associated with pathological lesions needs to be elucidated because of the putative links between these enzymes and the disease process in AD. In this study, cholinesterases were extracted from AD and normal brain tissue to determine whether the differences observed in histochemical analyses in the two sources were reflected in kinetic properties measured in solubilized enzymes. Isolated brain enzymes from both these sources exhibited comparable kinetic parameters with respect to pH dependence, substrate affinity and inhibitor sensitivity and were not significantly affected by other agents that blocked cholinesterase histochemical visualization, such as the structurally diverse metal-chelating antibiotics bacitracin, doxycycline, minocycline and rifampicin. Although the cholinesterases from AD brain tissue examined here represented a total pool of these enzymes from AD brain, rather than enzymes specifically from NPs and NFTs, their kinetic behavior being comparable to cholinesterases isolated from normal brain tissues implies that these enzymes do not undergo disease-related modification in their primary structures. This suggests that the atypical histochemical behavior of cholinesterases in NPs and NFTs may result from interaction of cholinesterases with other molecules within these lesions, mediated by transition metal ions known to be present in AD pathology lesions.

In this paper, we present an illustrative case of Semantic Dementia (SD) and we review the literature on this relatively rare progressive neurodegenerative disorder. After reviewing the clinical, neuroimaging, neuropathological, and genetic features of SD, we propose a theoretical framework that addresses features of SD and relates them to features of other well known neuropsychiatric syndromes. Our 'on-line / off-line disconnection' model seeks to conceptualize SD as a syndrome of disconnection between two large distributed cortical networks, namely, between those networks that subserve language function and those that subserve memory function.