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This chapter describes the core procedures that we have developed over the last two decades to isolate routinely the microglia from postmortem human brains. The method is suitable for brain slices consisting of both gray and white matter.The ability to concomitantly isolate vascular cells with glial cells provides the opportunity to investigate multiple cell types originating from the same donor. This represents a novel approach for -omics research, with the potential for discovering the shared or distinct molecular features among the glia and vascular cells from the same individual.

There has been a markedly renewed interest in factors associated with pneumonia, a leading cause of death worldwide, due to its frequent concurrence with pandemics of influenza and Covid-19 disease. Reported predisposing factors to both bacterial pneumonia and pandemic viral lower respiratory infections are wintertime occurrence, older age, obesity, pre-existing cardiopulmonary conditions and diabetes. Also implicated are age-related neurodegenerative diseases that cause parkinsonism and dementia. We investigated the prevalence of autopsy-proven pneumonia in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), a longitudinal clinicopathological study, between the years 2006 and 2019 and before the beginning of the Covid-19 pandemic. Of 691 subjects dying at advanced ages (mean 83.4), pneumonia was diagnosed postmortem in 343 (49.6%). There were 185 subjects without dementia or parkinsonism while clinicopathological diagnoses for the other subjects included 319 with Alzheimer’s disease dementia, 127 with idiopathic Parkinson’s disease, 72 with dementia with Lewy bodies, 49 with progressive supranuclear palsy and 78 with vascular dementia. Subjects with one or more of these neurodegenerative diseases all had higher pneumonia rates, ranging between 50 and 61%, as compared to those without dementia or parkinsonism (40%). In multivariable logistic regression models, male sex and a non-summer death both had independent contributions (ORs of 1.67 and 1.53) towards the presence of pneumonia at autopsy while the absence of parkinsonism or dementia was a significant negative predictor of pneumonia (OR 0.54). Male sex, dementia and parkinsonism may also be risk factors for Covid-19 pneumonia. The apolipoprotein E4 allele, as well as obesity, chronic obstructive pulmonary disease, diabetes, hypertension, congestive heart failure, cardiomegaly and cigarette smoking history, were not significantly associated with pneumonia, in contradistinction to what has been reported for Covid-19 disease.

Biochemical analysis of human brain tissue is typically done by homogenizing whole pieces of brain and separately characterizing the proteins, RNA, DNA, and other macromolecules within. While this has been sufficient to identify substantial changes, there is little ability to identify small changes or alterations that may occur in subsets of cells. To effectively investigate the biochemistry of disease in the brain, with its different cell types, we must first separate the cells and study them as phenotypically defined populations or even as individuals. In this project, we developed a new method for the generation of whole-cell-dissociated-suspensions (WCDS) in fresh human brain tissue that could be shared as a resource with scientists to study single human cells or populations. Characterization of WCDS was done in paraffin-embedded sections stained with H&E, and by phenotyping with antibodies using immunohistochemistry and fluorescence-activated cell sorting (FACS). Additionally, we compared extracted RNA from WCDS with RNA from adjacent intact cortical tissue, using RT-qPCR for cell-type-specific RNA for the same markers as well as whole transcriptome sequencing. More than 11,626 gene transcripts were successfully sequenced and classified using an external database either as being mainly expressed in neurons, astrocytes, microglia, oligodendrocytes, endothelial cells, or mixed (in two or more cell types). This demonstrates that we are currently capable of producing WCDS with a full representation of different brain cell types combined with RNA quality suitable for use in biochemical analysis.

The focus of this study is the expression of Toll-like receptor-3 (TLR-3), a receptor for double-stranded RNA, in human brains affected by Alzheimer’s disease (AD) pathology. Toll-like receptors are a family of pattern recognition molecules primarily involved in host defenses to microbial pathogens, but roles in neurodegenerative disease have also been shown, as amyloid beta (Aβ) can be a ligand for TLR-2 and −4 and α-synuclein for TLR-1 and TLR-2, while TLR-9 activation promotes Aβ removal. However, involvement of TLR-3 in AD has not been rigorously studied. Immunohistochemical analyses in human temporal cortical sections with a validated antibody for TLR-3 predominantly identified microglia, particularly strongly in cells associated with amyloid plaques, also brain vascular endothelial cells and subsets of astrocytes, but not neurons or p62-immunoreactive structures. Microglial TLR-3 colocalized with the endosomal/lysosomal marker CD68, which identifies phagocytic cells. Quantitative analyses of neuropathologically-staged human brain middle temporal gyrus samples using immunohistochemistry and mRNA expression methods demonstrated increased TLR-3 immunoreactivity and increased TLR-3 mRNA in AD compared to non-demented cases. There were significant positive correlations between TLR-3 mRNA levels and plaque or tangle loads in both series of samples. Increased expression of interferon beta (IFN-β) and interferon regulatory factor (IRF)-3 mRNA, two factors induced by TLR-3 signaling, were detected in the AD cases. Increased expression of TLR-4 and TLR-9 mRNA was also observed in these same samples, but not TLR-2. In vitro cultured human brain microglia responses to Aβ inflammatory activation were not altered by TLR-3 activation with activator polyinosinic;polycytidylic acid (poly I:C), while human brain endothelial cells showed reduction in responses when stimulated with both agents. Treatment of microglia with poly I:C did not increase their uptake and breakdown of Aβ.

The utility of the levels of amyloid beta (Aβ) peptide and tau in blood for diagnosis, drug development, and assessment of clinical trials for Alzheimer's disease (AD) has not been established. The lack of availability of ultra-sensitive assays is one critical issue that has impeded progress. The levels of Aβ species and tau in plasma and serum are much lower than levels in cerebrospinal fluid. Furthermore, plasma or serum contain high levels of assay-interfering factors, resulting in difficulties in the commonly used singulex or multiplex ELISA platforms. In this review, we focus on two modern immune-complex-based technologies that show promise to advance this field. These innovative technologies are immunomagnetic reduction technology and single molecule array technology. We describe the technologies and discuss the published studies using these technologies. Currently, the potential of utilizing these technologies to advance Aβ and tau as blood-based biomarkers for AD requires further validation using already collected large sets of samples, as well as new cohorts and population-based longitudinal studies.

Mitochondrial abnormalities are well known to cause cognitive decline. However, the underlying molecular basis of mitochondria-associated neuronal and synaptic dysfunction in the diabetic brain remains unclear. Here, using a mitochondrial single-channel patch clamp and cyclophilin D (CypD)-deficient mice (Ppif −/−) with streptozotocin-induced diabetes, we observed an increase in the probability of Ca2+-induced mitochondrial permeability transition pore (mPTP) opening in brain mitochondria of diabetic mice, which was further confirmed by mitochondrial swelling and cytochrome c release induced by Ca2+ overload. Diabetes-induced elevation of CypD triggers enhancement of F1F0 ATP synthase–CypD interaction, which in turn leads to mPTP opening. Indeed, in patients with diabetes, brain cypD protein levels were increased. Notably, blockade of the F1F0 ATP synthase–CypD interaction by CypD ablation protected against diabetes-induced mPTP opening, ATP synthesis deficits, oxidative stress, and mitochondria dysfunction. Furthermore, the absence of CypD alleviated deficits in synaptic plasticity, learning, and memory in diabetic mice. Thus, blockade of ATP synthase interaction with CypD provides a promising new target for therapeutic intervention in diabetic encephalopathy.

Introduction Quantitative EEG features have been identified as surrogates and predictors of cognitive decline/dementia, a common feature of progressive PD. The biochemical correlates for altered quantitative EEG features are unknown. Our primary objective was to test the hypothesis that quantitative EEG measures correlate with cortical levels of phosphorylated α-synuclein, a modified form of the synaptic protein α-synuclein, in PD cases, in contrast to other pathology-associated proteins. A secondary objective was to explore the same correlations among cellular fractions of these proteins. Methods We used posterior cingulate cortex autopsy tissue from 44 PD subjects with various degrees of cognitive decline, who had undergone EEG. In this brain region, which is a major hub of the default mode network, biochemical measurements for levels of phosphorylated α-synuclein, unmodified α-synuclein, amyloid beta peptide, phosphorylated tau, and key synaptic proteins were analyzed and data correlated with spectral EEG measures. Results Findings revealed significant correlations between background rhythm peak frequency and all bandpower values (highest in delta bandpower) with total phosphorylated α-synuclein, but not any correlation with total α-synuclein, phosphorylated tau protein, amyloid beta peptide, or synaptic proteins. Certain fractions of synaptosomal-associated protein 25 showed correlation with some quantitative EEG measures. Conclusions These data show an association between increased phosphorylation of α-synuclein and the abnormal EEG signatures of cognitive decline. Results suggest that quantitative EEG may provide an in vivo approximation of phosphorylated α-synuclein in PD cortex. This adds to previous evidence that quantitative EEG measures can be considered valid biomarkers of PD cognitive decline. © 2016 International Parkinson and Movement Disorder Society

Background: The stability of Alzheimer’s disease (AD) biomarkers in plasma, measured by immunomagnetic reduction (IMR) after long-term storage at –80°C, has not been established before. Method: Ninety-nine human plasma samples from 53 normal controls (NCs), 5 patients with amnestic mild cognitive impairment (aMCI), and 41 AD patients were collected. Each plasma sample was aliquoted and stored as single-use aliquots at –80°C. The baseline measurements for Aβ1–40, Aβ1–42, and total Tau protein (T-Tau) concentrations for each sample were done within 3 months of blood draw by IMR. They are referred to as baseline concentrations. A separate aliquot from each sample was assayed with IMR to assess the stability of the measured analytes during storage at –80°C between 1.1 and 5.4 years. This is referred to as a repeated result. Results: IMR shows that plasma levels of Aβ1–40 and Aβ1–42 exhibit stability over 5-year storage at –80°C and that plasma levels of T-Tau are less stable (approximately 1.5 years). Conclusion: Although the measured concentrations of T-Tau in human plasma may alter during storage, the diagnostic utility of the results are only slightly affected when the product of Aβ1–42 and T-Tau concentrations are used. The results show that the overall agreement between baseline and repeated measurements in the ability of discriminating NCs from aMCI/AD patients is higher than 80%.

Neuroinflammation plays a critical role in neuronal dysfunction and death of Alzheimer's disease (AD). ApoE4 is a major risk factor of AD, while ApoE2 is neuroprotective. Little is known about the roles of ApoE isoforms in the neuroinflammation seen in AD. Their roles and mechanisms in Aβ-induced/neuroinflammation were investigated in this study using in vivo and in vitro models. Rat astrocytes were treated with lipid-poor recombinant hApoE and/or Aβ42. Mouse astrocyte lines-expressing lipidated hApoE were treated with Aβ42 and/or vitamin D receptor (VDR) agonist, 1α,25-dihydroxyvitamin D3. Cells and media were harvested for cytokine ELISA, RNA isolated for qRT-PCR, and nuclear protein for transcription factor (TF) arrays and EMSA. hApoE-transgenic and AD mice were mated to generate hApoE2/AD and hApoE4/AD mice. Mice were euthanized at 6 months of age. Brain tissues were collected for cytokine ELISA array, Aβ ELISA, immunoblotting, and immunohistochemistry. hApoE4/AD mice had significantly higher levels of inflammatory cytokines than hApoE2/AD mice. Lipidated hApoE4 significantly promoted inflammatory gene expression induced by Aβ42 but not recombinant hApoE4 in astrocytes as compared to controls. Lipidated hApoE3 provided a certain degree of protection against Aβ42-induced inflammatory response but not recombinant hApoE3 as compared to controls. Both lipidated and recombinant hApoE2 provided protection against Aβ42-induced inflammatory response compared to controls. TF array revealed that ApoE2 strongly activated VDR in Aβ42-treated astrocytes. Application of 1α,25-dihydroxyvitamin D3 completely inhibited Aβ-induced inflammatory gene expression in hApoE4-expressing astrocytes. The results suggest that ApoE4 promotes, but ApoE2 inhibits, AD/Aβ-induced neuroinflammation via VDR signaling. Targeting VDR signaling or active form of VD3 may relieve AD neuroinflammation or/and neurodegeneration.

The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain-only donations and currently has banked more than 1600 brains. More than 430 whole-body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimer's disease, Parkinson's disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimer's Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinson's Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinson's Research. The Program has made rapid autopsy a priority, with a 3.0-hour median post-mortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant-funded projects.

Reduction in the deposition of amyloid β (Aβ) has been the primary target for Alzheimer's disease (AD) therapeutics recently, but in clinical trials this approach has generally been unsuccessful. A common feature of AD pathology is a complex inflammatory component that could be a target for treatment. One feature of this inflammation has been the involvement of the receptor for advanced glycation endproducts (RAGE), whose ligands include advanced glycation-endproduct-modified proteins as well as lipids and Aβ, which are found at elevated levels in AD brains.In this article, the authors describe the key features of RAGE and how it could have a role in AD pathogenesis. They also summarize experimental animal and clinical data that demonstrate the therapeutic effect of RAGE inhibition and consider what these findings mean for human disease.RAGE has multiple ligands, including Aβ, that are increased in AD brains. Inhibiting RAGE-ligand interactions without activating receptor signaling can reduce multiple pathological pathways relevant for AD. Several RAGE inhibitors and modulators are now being tested as therapeutics for AD. Recent Phase II studies have established the good safety and tolerability of TTP448 with some evidence of positive benefit at lower dose. This suggests that further studies are required.

Neuroinflammation is considered a key pathological process in neurodegenerative diseases of aging, including Alzheimer&rsquo, s disease (AD). Many studies have defined phenotypes of reactive microglia, the brain-resident macrophages, with different antigenic markers to identify those potentially causing inflammatory damage. We took an alternative approach with the goal of characterizing the distribution of purinergic receptor P2RY12-positive microglia, a marker previously defined as identifying homeostatic or non-activated microglia. We examined the expression of P2RY12 by dual-color light and fluorescence immunohistochemistry using sections of middle temporal gyrus from AD, high plaque and low plaque non-demented cases in relation to amyloid beta (A&beta, ) plaques and phosphorylated tau, markers of pathology, and HLA-DR, IBA-1, CD68, and progranulin, microglial phenotype markers. In low plaque cases, P2RY12-positive microglia mostly had non-activated morphologies, while the morphologies of P2RY12-positive microglia in AD brains were highly variable, suggesting its expression could encompass a wider range of phenotypes than originally hypothesized. P2RY12 expression by microglia differed depending on the types of plaques or tangles they were associated with. Areas of inflammation characterized by lack of P2RY12-positive microglia around mature plaques could be observed, but many diffuse plaques showed colocalization with P2RY12-positive microglia. Based on these results, P2RY12 expression by microglia should not be considered solely a marker of resting microglia as P2RY12 immunoreactivity was identifying microglia positive for CD68, progranulin and to a limited extent HLA-DR, markers of activation.

Background: Past studies investigating the association between Alzheimer’s disease (AD) pathology and diabetes mellitus type 2 (DM2) have provided conflicting results. While several studies indicate that subjects with comorbid AD and DM2 have less AD pathology, others have found no significant differences in AD pathology between the two groups. Other studies have indicated that individuals with AD and DM2 have significantly greater neuropathology than AD individuals who do not have DM2. Additional research has demonstrated that ApoE e 4 carriers with AD and DM2 have significantly greater pathology than ApoE e 4 non-carriers. Methods: Data on clinically and pathologically diagnosed Alzheimer’s disease cases (NINDS-ADRDA clinically and NIA Reagan intermediate or high pathologically) with DM2 (n= 40) and those without DM2 (n= 322) from the Banner Sun Health Research Institute Brain and Body Donation Program were obtained for this study. Plaque and tangle scores from the frontal, parietal, temporal, entorhinal and hippocampal regions were compared between the DM2+ and DM2 – groups. In addition, total plaque count, total tangle count, and Braak scores were also compared between groups. Similar analyses were conducted to determine the effect of ApoE e 4 carrier status on the neuropathological variables while also accounting for and DM2 status. Results: The DM2+ and DM2 – groups showed no significant differences on plaque and tangle pathology. Logistic regression analyses, which accounted for the effects of ApoE e4 carrier status and age at death, found no association between total plaque [OR 1.05 (0.87, 1.27), p = 0.60] or total tangle [OR 0.97 (0.89, 1.07) p = 0.58] counts and DM2 status. ApoE e4 carrier status was not significantly associated with DM2 status [ Χ2 = 0.30 (df = 1), p = 0.58]. Within the DM2+ group, significantly greater plaque and tangle pathology was found for ApoE e4 carriers in relation to DM2+ ApoE e4 non-carriers. Conclusion: Overall, the presence of DM2 does not affect plaque and tangle burden in a sample of clinically and pathologically confirmed AD cases. Among AD individuals with DM2, those who are ApoE e 4 carriers had significantly greater neuropathology than those who do not carry an ApoE e4 allele. Positive DM2 status appears to exacerbate AD neuropathology in the presence of ApoE e 4.

Mitochondrial dysfunction and synaptic damage are early pathological features of the Alzheimer's disease-affected brain. Memory impairment in Alzheimer's disease is a manifestation of brain pathologies such as accumulation of amyloid-β peptide and mitochondrial damage. The underlying pathogenic mechanisms and effective disease-modifying therapies for Alzheimer's disease remain elusive. Here, we demonstrate for the first time that decreased PTEN-induced putative kinase 1 (PINK1) expression is associated with Alzheimer's disease pathology. Restoring neuronal PINK1 function strikingly reduces amyloid-β levels, amyloid-associated pathology, oxidative stress, as well as mitochondrial and synaptic dysfunction. In contrast, PINK1-deficient mAPP mice augmented cerebral amyloid-β accumulation, mitochondrial abnormalities, impairments in learning and memory, as well as synaptic plasticity at an earlier age than mAPP mice. Notably, gene therapy-mediated PINK1 overexpression promotes the clearance of damaged mitochondria by augmenting autophagy signalling via activation of autophagy receptors (OPTN and NDP52), thereby alleviating amyloid-β-induced loss of synapses and cognitive decline in Alzheimer's disease mice. Loss of PINK1 activity or blockade of PINK1-mediated signalling (OPTN or NDP52) fails to reverse amyloid-β-induced detrimental effects. Our findings highlight a novel mechanism by which PINK1-dependent signalling promotes the rescue of amyloid pathology and amyloid-β-mediated mitochondrial and synaptic dysfunctions in a manner requiring activation of autophagy receptor OPTN or NDP52. Thus, activation of PINK1 may represent a new therapeutic avenue for combating Alzheimer's disease.

Alzheimer’s disease (AD) is characterized by extracellular deposits of amyloid-β (Aβ) in the brain. ABCA7 is highly expressed in the brain and a susceptibility gene for late-onset AD (LOAD). The minor alleles at two ABCA7 single-nucleotide polymorphisms (SNPs), rs3764650 (T>G; intron13) and rs3752246 at a predicted myristoylation site (C>G; exon33; p.Gly1527Ala), are significantly associated with LOAD risk; however, the mechanism of this association is unknown. Functional consequences of both SNPs were examined in HEK293 and CHO cells stably expressing AβPP Swe. Luciferase reporter assays in HEK293 cells suggested that intron13 carrying rs3764650 major T-allele (int13-T) possessed promoter-enhancing capabilities. Co-transfection experiments with hABCA7 and int13-T resulted in significantly increased ABCA7 protein level relative to that with int13-G. Expression of hABCA7 carrying rs3752246 risk allele led to increases in secreted Aβ 40 and Aβ 42 and β-secretase activity in CHO- and HEK-AβPP Swe cells. Hydroxymyristic acid treatment of cells expressing hABCA7 carrying the rs3752246 major G allele resulted in increased β-secretase activity and levels of Aβ, suggesting that lack of myristoylation contributes to the observed cell-phenotypes. Molecular weight determination, by gel-electrophoresis and mass spectrometry, of hABCA7 peptides spanning position 1527 showed loss of post-translational modification in the risk-allele peptide. These results suggest that decreased expression, or impaired function, of ABCA7 may contribute to AD pathology., Erratum published in vol. 66, no. 2, pp. 853-854, 2018. DOI: 10.3233/JAD-189009

A key component in Lewy body (LB) pathology in LB disorders is α-synuclein phosphorylated at serine 129 (pαsyn). However, it is not known if increase in the level of biochemically measurable pαsyn precedes the presence of histologically identified Lewy-type synucleinopathy (LTS). To gain sights into possible temporal sequence, we measured levels of pαsyn in cingulate and temporal cortices that develop LTS pathology at later stages of LB disorders. Brain homogenates from 128 autopsy cases including normal controls and subjects classified by Unified LTS histopathology staging system were studied. We found that biochemically measurable pαsyn levels in cingulate and temporal cortices were significantly increased at Unified stages III and IV. When pαsyn levels were compared between LTS density scores instead of Unified stages, significant increases were detected even as LTS density scores increased from 0 to 1 in olfactory bulb and substantia nigra. Therefore, our findings demonstrated that changes of pαsyn levels in cingulate and temporal cortices coincided with the early appearance of the LTS pathology in olfactory bulb and substantia nigra, even though histologically demonstrable LTS was lacking in the cortical region. Therefore, identifying the underlying mechanisms driving these changes could be crucial to understanding the pathogenesis of LB disorders.

There is an urgent need for new ways to treat Alzheimer’s disease (AD), the most common cause of dementia in the elderly. Current therapies are modestly effective at treating the symptoms, and do not significantly alter the course of the disease. Over the years, a range of epidemiological and experimental studies have demonstrated interactions between diabetes mellitus and AD. As both diseases are leading causes of morbidity and mortality in the elderly and are frequent co-morbid conditions, it has raised the possibility that treating diabetes might be effective in slowing AD. This is currently being attempted with drugs such as the insulin sensitizer rosiglitazone. These two diseases share many clinical and biochemical features, such as elevated oxidative stress, vascular dysfunction, amyloidogenesis and impaired glucose metabolism suggesting common pathogenic mechanisms. The main thrust of this review will be to explore the evidence from a pathological point of view to determine whether diabetes can cause or exacerbate AD. This was supported by a number of animal models of AD that have been shown to have enhanced pathology when diabetic conditions were induced. The one drawback in linking diabetes and insulin to AD has been the postmortem studies of diabetic brains demonstrating that AD pathology was not increased; in fact decreased pathology has often been reported. In addition, diabetes induces its own distinct features of neuropathology different from AD. There are common pathological features to be considered including vascular abnormalities, a major feature arising from diabetes; there is increasing evidence that vascular abnormalities can contribute to AD. The most important common mechanism between insulin-resistant (type II) diabetes and AD could be impaired insulin signaling; a form of toxic amyloid can damage neuronal insulin receptors and affect insulin signaling and cell survival. It has even been suggested that AD could be considered as “type 3 diabetes” since insulin can be produced in brain. Another common feature of diabetes and AD are increased advanced glycation endproduct-modified proteins are found in diabetes and in the AD brain; the receptor for advanced glycation endproducts plays a prominent role in both diseases. In addition, a major role for insulin degrading enzyme in the degradation of Aβ peptide has been identified. Although clinical trials of certain types of diabetic medications for treatment of AD have been conducted, further understanding the common pathological processes of diabetes and AD are needed to determine whether these diseases share common therapeutic targets.

The ability to understand how Parkinson's disease neurodegeneration leads to cortical dysfunction will be critical for developing therapeutic advances in Parkinson's disease dementia. The overall purpose of this project was to study the small-amplitude cortical myoclonus in Parkinson's disease as an in vivo model of focal cortical dysfunction secondary to Parkinson's disease neurodegeneration. The objectives were to test the hypothesis that cortical myoclonus in Parkinson's disease is linked to abnormal levels of α-synuclein in the primary motor cortex and to define its relationship to various biochemical, clinical, and pathological measures. The primary motor cortex was evaluated for 11 Parkinson's disease subjects with and 8 without electrophysiologically confirmed cortical myoclonus (the Parkinson's disease + myoclonus group and the Parkinson's disease group, respectively) who had premortem movement and cognitive testing. Similarly assessed 9 controls were used for comparison. Measurements for α-synuclein, Aβ-42 peptide, and other biochemical measures were made in the primary motor cortex. A 36% increase in α-synuclein was found in the motor cortex of Parkinson's disease + myoclonus cases when compared with Parkinson's disease without myoclonus. This occurred without significant differences in insoluble α-synuclein, phosphorylated to total α-synuclein ratio, or Aβ-42 peptide levels. Higher total motor cortex α-synuclein levels significantly correlated with the presence of cortical myoclonus but did not correlate with multiple clinical or pathological findings. These results suggest an association between elevated α-synuclein and the dysfunctional physiology arising from the motor cortex in Parkinson's disease + myoclonus cases. Alzheimer's disease pathology was not associated with cortical myoclonus in Parkinson's disease. Cortical myoclonus arising from the motor cortex is a model to study cortical dysfunction in Parkinson's disease. © 2011 Movement Disorder Society

Amyloid- beta (A beta) peptide-binding alcohol dehydrogenase (ABAD), an enzyme present in neuronal mitochondria, exacerbates A beta-induced cell stress. The interaction of ABAD with A beta exacerbates A beta-induced mitochondrial and neuronal dysfunction. Here, we show that inhibition of the ABAD-A beta interaction, using a decoy peptide (DP) in vitro and in vivo, protects against aberrant mitochondrial and neuronal function and improves spatial learning/memory. Intraperitoneal administration of ABAD-DP [fused to the transduction of human immunodeficiency virus 1-transactivator (Tat) protein and linked to the mitochondrial targeting sequence (Mito) (TAT-mito-DP) to transgenic APP mice (Tg mAPP)] blocked formation of ABAD-A beta complex in mitochondria, increased oxygen consumption and enzyme activity associated with the mitochondrial respiratory chain, attenuated mitochondrial oxidative stress, and improved spatial memory. Similar protective effects were observed in Tg mAPP mice overexpressing neuronal ABAD decoy peptide (Tg mAPP/mito-ABAD). Notably, inhibition of the ABAD-A beta interaction significantly reduced mitochondrial A beta accumulation. In parallel, the activity of mitochondrial A beta-degrading enzyme PreP (presequence peptidase) was enhanced in Tg mAPP mitochondria expressing the ABAD decoy peptide. These data indicate that segregating ABAD from A beta protects mitochondria/neurons from A beta toxicity; thus, ABAD-A beta interaction is an important mechanism underlying A beta-mediated mitochondrial and neuronal perturbation. Inhibitors of ABAD-A beta interaction may hold promise as targets for the prevention and treatment of Alzheimer's disease. Publisher PDF

Dementia in Parkinson's disease (PD-D) has only been acknowledged in the recent three decades, but research in this field has accelerated. The purpose of this review was to discuss advances in PD-D regarding biomarker correlates and potential therapeutic targets. Attention and executive dysfunction, memory deficits that improve with cueing, and visual hallucinations are characteristic in PD-D. PD-D dramatically increases the disability and misery of the disease. Current treatment for PD-D is symptomatic, modest, and only transiently effective. There is wide agreement that more effective treatment is needed, but this will require more knowledge about PD-D pathophysiology. Advances in the pathogenesis of PD have focused on the substantia nigra, which is the location from where the pathophysiology of motor symptoms primarily arises in initial stages. In contradistinction, pathology studies have suggested that cognitive decline correlates with cortical and subcortical-cortical projection pathway abnormalities. There is evidence that substantia nigra mechanisms, including protein aggregation of α-synuclein (e.g., Lewy bodies) may also play a role in cortical neuron degeneration. Other different mechanisms, such as Alzheimer's disease pathology (e.g., Aβ aggregation) may be operant for PD-D. Biomarkers of various types are being proposed for the study of PD-D as well as for objective measures of PD-D prediction and progression. Therapeutic targets are currently derived mostly from general PD neurodegeneration research rather than cortical PD neurodegeneration per se. Protein aggregation, genes that are associated with PD, oxidative stress, inflammation, and trophic factors constitute the major classes of therapeutic targets for PD-D. More research is needed on the specific aspects of cortical dysfunction and degeneration that create PD-D.

Inflammatory regulators, including endogenous anti-inflammatory systems, can down-regulate inflammation thus providing negative feedback. Chronic inflammation can result from imbalance between levels of inflammatory mediators and regulators during immune responses. As a consequence, there are heightened inflammatory responses and irreversible tissue damage associated with many age-related chronic diseases. Alzheimer's disease (AD) brain is marked by prominent inflammatory features, in which microglial activation is the driving force for the elaboration of an inflammatory cascade. How the regulation of inflammation loses its effectiveness during AD pathogenesis remains largely unclear. In this article, we will first review current knowledge of microglial activation and its association with AD pathology. We then discuss four examples of anti-inflammatory systems that could play a role in regulating microglial activation: CD200/CD200 receptor, vitamin D receptor, peroxisome proliferator-activated receptors, and soluble receptor for advanced glycation end products. Through this, we hope to illustrate the diverse aspects of inflammatory regulatory systems in brain and neurodegenerative diseases such as AD. We also propose the importance of neuronal defense systems, because they are part of the integral inflammatory and anti-inflammatory systems. Augmenting the anti-inflammatory defenses of neurons can be included in the strategy for restoration of balanced immune responses during aging and neurodegenerative diseases.