Lee S, Tong M, Hang S
… +2 more, Deochand C, de la Monte S
J Alzheimers Dis Parkinsonism
· 2013 Oct · PMID 25035815
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Alzheimer's disease (AD) is characterized by progressive impairments in cognitive and behavioral functions with deficits in learning, memory and executive reasoning. Growing evidence points toward brain insulin and insul...Alzheimer's disease (AD) is characterized by progressive impairments in cognitive and behavioral functions with deficits in learning, memory and executive reasoning. Growing evidence points toward brain insulin and insulin-like growth factor (IGF) resistance-mediated metabolic derangements as critical etiologic factors in AD. This suggests that indices of insulin/IGF resistance and their consequences, i.e. oxidative stress, neuro-inflammation, and reduced neuronal plasticity, should be included in biomarker panels for AD. Herein, we examine a range of metabolic, inflammatory, stress, and neuronal plasticity related proteins in early AD, late AD, and aged control postmortem brain, postmortem ventricular fluid (VF), and clinical cerebrospinal fluid (CSF) samples. In AD brain, VF, and CSF samples the trends with respect to alterations in metabolic, neurotrophin, and stress indices were similar, but for pro-inflammatory cytokines, the patterns were discordant. With the greater severities of dementia and neurodegeneration, the differences from control were more pronounced for late AD (VF and brain) than early or moderate AD (brain, VF and CSF). The findings suggest that the inclusion of metabolic, neurotrophin, stress biomarkers in AβPP-Aβ+pTau CSF-based panels could provide more information about the status and progression of neurodegeneration, as well as aid in predicting progression from early- to late-stage AD. Furthermore, standardized multi-targeted molecular assays of neurodegeneration could help streamline postmortem diagnoses, including assessments of AD severity and pathology.
Perea RD, Rada RC, Wilson J
… +6 more, Vidoni1 ED, Morris JK, Lyons KE, Pahwa R, Burns JM, Honea RA
J Alzheimers Dis Parkinsonism
· 2013 Aug · PMID 24724042
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Alzheimer's disease (AD) and Parkinson's disease (PD) are among the most common neurodegenerative disorders affecting older populations. AD is characterized by impaired memory and cognitive decline while the primary symp...Alzheimer's disease (AD) and Parkinson's disease (PD) are among the most common neurodegenerative disorders affecting older populations. AD is characterized by impaired memory and cognitive decline while the primary symptoms of PD include resting tremor, bradykinesia and rigidity. In PD, mild cognitive changes are frequently present, which could progress to dementia (PD dementia (PDD)). PDD and AD dementias are different in pathology although the difference in microstructural changes remains unknown. To further understand these diseases, it is essential to understand the distinct mechanism of their microstructural changes. We used diffusion tensor imaging (DTI) to investigate white matter tract differences between early stage individuals with AD (n=14), PD (n=12), PDD (n=9), and healthy non-demented controls (CON) (n=13). We used whole brain tract based spatial statistics (TBSS) and a region of interest (ROI) analysis focused on the substantia nigra (SN). We found that individuals with PDD had more widespread white matter degeneration compared to PD, AD, and CON. Individuals with AD had few regional abnormalities in the anterior and posterior projections of the corpus callosum while PD and CON did not appear to have significant white matter degeneration when compared to other groups. ROI analyses showed that PDD had the highest diffusivity in the SN and were significantly different from CON. There were no significant ROI differences between CON, PD, or AD. In conclusion, global white matter microstructural deterioration is evident in individuals with PDD, and DTI may provide a means with which to tease out pathological differences between AD and PD dementias.
J Alzheimers Dis Parkinsonism
· 2013 Mar · PMID 24639916
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Recent developments in brain imaging methods are on the verge of changing the evaluation of people with Parkinson's disease (PD). This includes an assortment of techniques ranging from diffusion tensor imaging (DTI) to i...Recent developments in brain imaging methods are on the verge of changing the evaluation of people with Parkinson's disease (PD). This includes an assortment of techniques ranging from diffusion tensor imaging (DTI) to iron-sensitive methods such as T, as well as adiabatic methods R and R, resting-state functional MRI, and magnetic resonance spectroscopy (MRS). Using a multi-modality approach that ascertains different aspects of the pathophysiology or pathology of PD, it may be possible to better characterize disease phenotypes as well as provide a surrogate of disease and a potential means to track disease progression.
J Alzheimers Dis Parkinsonism
· 2013 Mar · PMID 24600537
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Chronic neuroinflammation is characteristic of neurodegenerative diseases and is present during very early stages, yet significant pathology and behavioral deficits do not manifest until advanced age. We investigated the...Chronic neuroinflammation is characteristic of neurodegenerative diseases and is present during very early stages, yet significant pathology and behavioral deficits do not manifest until advanced age. We investigated the consequences of experimentally-induced chronic neuroinflammation within the hippocampus and brainstem of young (4 mo) F-344 rats. Lipopolysaccharide (LPS) was infused continuously into the IV ventricle for 2, 4 or 8 weeks. The number of MHC II immunoreactive microglia in the brain continued to increase throughout the infusion period. In contrast, performance in the Morris water maze was impaired after 4 weeks but recovered by 8 weeks. Likewise, a transient loss of tyrosine hydroxylase immunoreactivity in the substantia nigra and locus coeruleus was observed after 2 weeks, but returned to control levels by 4 weeks of continuous LPS infusion. These data suggest that direct activation of microglia is sufficient to drive, but not sustain, spatial memory impairment and a decrease in tyrosine hydroxylase production in young rats. Our previous studies suggest that chronic neuroinflammation elevates extracellular glutamate and that this elevation underlies the spatial memory impairment. In the current study, increased levels of GLT1 and SNAP25 in the hippocampus corresponded with the resolution of performance deficit. Increased expression of SNAP25 is consistent with reduced glutamate release from axonal terminals while increased GLT1 is consistent with enhanced clearance of extracellular glutamate. These data demonstrate the capacity of the brain to compensate for the presence of chronic neuroinflammation, despite continued activation of microglia, through changes in the regulation of the glutamatergic system.
J Alzheimers Dis Parkinsonism
· 2013 Oct · PMID 24563821
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Brain-derived interleukin-2 (IL-2) has been implicated in diseases processes that arise during CNS development (e.g., autism) to neurodegenerative alterations involving neuroinflammation (e.g., Alzheimer's disease). Prog...Brain-derived interleukin-2 (IL-2) has been implicated in diseases processes that arise during CNS development (e.g., autism) to neurodegenerative alterations involving neuroinflammation (e.g., Alzheimer's disease). Progress has been limited, however, because the vast majority of current knowledge of IL-2's actions on brain function and behavior is based on the use exogenously administered IL-2 to make inferences about the function of the endogenous cytokine. Thus, to identify the cell-type(s) and regional circuitry that express brain-derived IL-2, we used B6.Cg-Tg/ IL2-EGFP17Evr (IL2p8-GFP) transgenic mice, which express green fluorescent protein (GFP) in peripheral immune cells known to produce IL-2. We found that the IL2-GFP transgene was localized almost exclusively to NeuN-positive cells, indicating that the IL-2 is produced primarily by neurons. The IL2-GFP transgene was expressed in discrete nuclei throughout the rostral-caudal extent of the brain and brainstem, with the highest levels found in the cingulate, dorsal endopiriform nucleus, lateral septum, nucleus of the solitary tract, magnocellular/gigantocellular reticular formation, red nucleus, entorhinal cortex, mammilary bodies, cerebellar fastigial nucleus, and posterior interposed nucleus. Having identified IL-2 gene expression in brain regions associated with the regulation of sensorimotor gating (e.g., lateral septum, dorsal endopiriform nucleus, entorhinal cortex, striatum), we compared prepulse inhibition (PPI) of the acoustic startle response in congenic mice bred in our lab that have selective loss of the IL-2 gene in the brain versus the peripheral immune system, to test the hypothesis that brain-derived IL-2 plays a role in modulating PPI. We found that congenic mice devoid of IL-2 gene expression in both the brain and the peripheral immune system, exhibited a modest alteration of PPI. These finding suggest that IL2p8-GFP transgenic mice may be a useful tool to elucidate further the role of brain-derived IL-2 in normal CNS function and disease.
J Alzheimers Dis Parkinsonism
· 2013 Aug · PMID 24558640
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We propose that sleep disruption is a lever arm that influences how cognition emerges in development and then declines in response to Alzheimer disease in people with Down syndrome. Addressing sleep disruptions might be...We propose that sleep disruption is a lever arm that influences how cognition emerges in development and then declines in response to Alzheimer disease in people with Down syndrome. Addressing sleep disruptions might be an overlooked way to improve cognitive outcomes in this population. This article is a contribution to a Special Issue on Down Syndrome curated by the editors of the Journal of Alzheimer's Disease & Parkinsonism.
J Alzheimers Dis Parkinsonism
· 2013 Jun · PMID 24058743
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Loss of neuronal phenotype and reversal of neuronal atrophy have been demonstrated in different models of central nervous system (CNS) injury. These processes may be generalizable to different types of brain neurons and...Loss of neuronal phenotype and reversal of neuronal atrophy have been demonstrated in different models of central nervous system (CNS) injury. These processes may be generalizable to different types of brain neurons and circuitry. The idea that some injured neurons may lose their phenotype and/or atrophy with the potential to rejuvenate is a remarkable and potentially promising form of neuronal plasticity that is not well understood. In this paper, we present some of our laboratory's basic neuroimmunology research showing that peripheral T cells entering the CNS, and brain-derived interleukin-2 (IL-2), play significant roles in these intriguing processes. Our findings suggest, for example, that T cell immunosenesence could be involved in related processes of brain aging and contribute to neurodegenerative disease. Neuroimmunological approaches may provide new insights into yet undiscovered factors and brain mechanisms that regulate changes in neuronal integrity associated with aging and disease. Such findings could have important implications for discovering more effective strategies for treating patients with neurotrauma and neurodegenerative diseases (e.g., Alzheimer's disease).
Carman A, Kishinevsky S, Koren J
… +2 more, Lou W, Chiosis G
J Alzheimers Dis Parkinsonism
· 2013 Apr · PMID 25258700
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Maintenance of cellular homeostasis is regulated by the molecular chaperones. Under pathogenic conditions, aberrant proteins are triaged by the chaperone network. These aberrant proteins, known as "clients," have major r...Maintenance of cellular homeostasis is regulated by the molecular chaperones. Under pathogenic conditions, aberrant proteins are triaged by the chaperone network. These aberrant proteins, known as "clients," have major roles in the pathogenesis of numerous neurological disorders, including tau in Alzheimer's disease, α-synuclein and LRRK2 in Parkinson's disease, SOD-1, TDP-43 and FUS in amyotrophic lateral sclerosis, and polyQ-expanded proteins such as huntingtin in Huntington's disease. Recent work has demonstrated that the use of chemical compounds which inhibit the activity of molecular chaperones subsequently alter the fate of aberrant clients. Inhibition of Hsp90 and Hsc70, two major molecular chaperones, has led to a greater understanding of how chaperone triage decisions are made and how perturbing the chaperone system can promote clearance of these pathogenic clients. Described here are major pathways and components of several prominent neurological disorders. Also discussed is how treatment with chaperone inhibitors, predominately Hsp90 inhibitors which are selective for a diseased state, can relieve the burden of aberrant client signaling in these neurological disorders.
Decourt B, Mobley W, Reiman E
… +2 more, Shah RJ, Sabbagh MN
J Alzheimers Dis Parkinsonism
· 2013 Mar · PMID 24782952
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Down syndrome is one of the most common genetic conditions occurring in one in 700 live births. The trisomy of chromosome 21 causes over-expression of APP which in turn is indicated in the increased production of Aβ asso...Down syndrome is one of the most common genetic conditions occurring in one in 700 live births. The trisomy of chromosome 21 causes over-expression of APP which in turn is indicated in the increased production of Aβ associated with AD. This makes DS the most common presenile form of AD exceeding PS1 and PS2 FAD. Since a majority of DS individuals develop dementia, it is important to examine whether DS and sporadic AD share common features, for example, to anticipate shared treatments in the future. Here we explore commonalities and differences for secretases and endosomal pathways in DS and AD.
Lukiw WJ, Bjattacharjee S, Zhao Y
… +2 more, Pogue AI, Percy ME
J Alzheimers Dis Parkinsonism
· 2012 Jan · PMID 24619568
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The cellular generation of reactive oxygen species (ROS) has been implicated in contributing to the pathology of human neurological disorders including Alzheimer's disease (AD) and Parkinson's disease (PD). To further un...The cellular generation of reactive oxygen species (ROS) has been implicated in contributing to the pathology of human neurological disorders including Alzheimer's disease (AD) and Parkinson's disease (PD). To further understand the triggering and participation of ROS-generating species to pro-inflammatory and pathological signaling in human brain cells, in these experiments we studied the effects of 22 different substances (including various common drugs, interleukins, amyloid precursor protein, amyloid peptides and trace metals) at nanomolar concentrations, in a highly sensitive human neuronal-glial (HNG) cell primary co-culture assay. The evolution of ROS was assayed using the cell-permeate fluorescent indicator 2',7'-dichlorofluorescein diacetate (HDCFDA), that reacts with major ROS species, including singlet oxygen, hydroxyl radicals or superoxides (λEx 488 nm; λEm 530 nm). Western analysis was performed for cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and cytosolic phospholipase A (cPLA) to study the effects of induced ROS on inflammatory gene expression within the same brain cell sample. The data indicate that apart from acetylsalicylic acid (aspirin) and simvastatin, several neurophysiologically-relevant concentrations of Aβpeptides and neurotoxic trace metals variably induced ROS induction, COX-2 and cPLA expression. These findings have mechanistic implications for ROS-triggered inflammatory gene expression programs that may contribute to AD and PD neuropathologic mechanisms.
Westmark CJ, Hervey CM, Berry-Kravis EM
… +1 more, Malter JS
J Alzheimers Dis Parkinsonism
· 2011 Jul · PMID 23459194
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Altered levels of amyloid β-protein precursor (AβPP) and/or amyloid beta (Aβ) are characteristic of several neurological disorders including Alzheimer's disease (AD), Down syndrome (DS), Fragile X syndrome (FXS), Parkins...Altered levels of amyloid β-protein precursor (AβPP) and/or amyloid beta (Aβ) are characteristic of several neurological disorders including Alzheimer's disease (AD), Down syndrome (DS), Fragile X syndrome (FXS), Parkinson's disease (PD), autism and epilepsy. Thus, these proteins could serve as valuable blood-based biomarkers for assessing disease severity and pharmacological efficacy. We have observed significant differences in Aβ levels in human plasma dependent on the anticoagulant utilized during blood collection. Our data suggests that anticoagulants alter AβPP processing and that care needs to be used in comparing published studies that have not utilized the same blood collection methodology.