Early Event In Alzheimer's Disease Pathogenesis Research Articles

Implication of tau propagation on neurodegeneration in Alzheimer's disease.

Propagation of tau fibrils correlate closely with neurodegeneration and memory deficits seen during the progression of Alzheimer's disease (AD). Although it is not well-established what drives or attenuates tau spreading, new studies on human brain using positron emission tomography (PET) have shed light on how tau phosphorylation, genetic factors, and the initial epicenter of tau accumulation influence tau accumulation and propagation throughout the brain. Here, we review the latest PET studies performed across the entire AD continuum looking at the impact of amyloid load on tau pathology. We also explore the effects of structural, functional, and proximity connectivity on tau spreading in a stereotypical manner in the brain of AD patients. Since tau propagation can be quite heterogenous between individuals, we then consider how the speed and pattern of propagation are influenced by the starting localization of tau accumulation in connected brain regions. We provide an overview of some genetic variants that were shown to accelerate or slow down tau spreading. Finally, we discuss how phosphorylation of certain tau epitopes affect the spreading of tau fibrils. Since tau pathology is an early event in AD pathogenesis and is one of the best predictors of neurodegeneration and memory impairments, understanding the process by which tau spread from one brain region to another could pave the way to novel therapeutic avenues that are efficient during the early stages of the disease, before neurodegeneration induces permanent brain damage and severe memory loss.

Decreased Levels of Blood AMPKα1 but not AMPKα2 Isoform in Patients with Mild Cognitive Impairment and Alzheimer's Disease: A Pilot Study.

There is an urgent need to develop feasible biomarkers for diagnosis and prognosis of Alzheimer's disease (AD). Mounting evidence implicates that dysregulation of energy metabolism is a key and early event in AD pathogenesis. AMP-activated protein kinase (AMPK) is a central molecular sensor that plays a critical role in maintaining cellular energy homeostasis, and aberrant brain AMPK activities are linked to AD pathophysiology. We aimed to investigated protein levels of AMPKα isoforms, AMPKα1 and AMPKα2, in plasma samples from patients clinically diagnosed with mild cognitive impairment (MCI) or AD, along with age-matched healthy controls. 30 participants (10 MCI, 10 AD, and 10 controls) were included in our pilot study. Plasma levels of AMPKα1 and AMPKα2 were determined by ELISA. Receiver operating characteristic (ROC) analysis was used to assess sensitivity and specificity. Linear regression was used to assess the correlation between levels of AMPKα isoforms and other biomarkers. Plasma levels of AMPKα1 were decreased in MCI and AD patients, while levels of AMPKα2 were unaltered as compared to controls. ROC analysis showed relatively high sensitivity and specificity for AMPKα1 to distinguish MCI and AD from controls. Linear regression analysis showed that plasma levels of AMPKα1 were correlated with a brain imaging biomarker (AD signature cortical thicknesses). Plasma levels of AMPKα1 were decreased in MCI and AD patients. Future endeavor to explore whether blood AMPKα1 protein expression has the value as a potential biomarker for AD and MCI diagnosis shall be encouraged.

Mitochondria in alzheimer’s disease

The pathogenesis of Alzheimer disease (AD) is associated with aberrant proteolytic processing of the amyloid precursor protein (APP) - first by b-secretase to generate a 99-aa C-terminal fragment (C99) and then by g-secretase (containing presenilins-1 [PS1] or -2 [PS2]) that cleaves C99 to generate the APP intracellular domain and the b-amyloid (Ab) that is found in extraneuronal plaques - but the relationship of the former to the latter is unclear. Whereas plaques typically form late in disease progression, early events include aberrant lipid metabolism and mitochondrial dysfunction. We recently showed that PS1, PS2, and g-secretase activity itself are highly enriched in a subdomain of the endoplasmic reticulum (ER) that communicates with mitochondria, called mitochondria-associated ER membranes (MAM), and that ER-mitochondrial connectivity and MAM function are highly upregulated in presenilin-mutant cells and in cells from AD patients. However, the relationship of perturbed APP processing to MAM-related AD phenotypes has been unclear. MAM, which is a lipid raft rich in cholesterol and sphingomyelin, is a key regulator of lipid metabolism and of mitochondial dynamics, among other processes. We now show that C99 is highly enriched in the MAM, and that it plays a central role in regulating cellular cholesterol and sphingolipid homeostasis and mitochondrial bioenergetics. Furthermore, in cells from AD patients and in cell and animal models of AD, C99 levels are increased significantly, resulting in a disruption of lipid homeostasis that is triggered by the unregulated uptake of extracellular cholesterol, with downstream consequences that mimic the biochemical features of AD, including the bioenergetic deficits. We propose that MAM-localized C99 is a component of the cell's lipid sensing machinery and that its accumulation is a key and early event in AD pathogenesis that can explain many of the biochemical and morphological features of the disease.

Suppressive Effects of Beta Amyloid Peptides (1-42) and (25-35) on Kv1.1 Channel Activity

Beta amyloid (Aβ) peptides have long been implicated in Alzheimer's Disease (AD) pathology, linking them to disruption of: Ca2+ homeostasis, synaptic communication, and long-term potentiation (LTP). But the mechanism(s) underlying these effects are still unclear. Because Kv1.1 and related channels are activated during an action potential, regulate depolarization-produced Ca2+ influx, and inhibition of Kv1 channels can be neurotoxic, we speculate that Aβ-suppression of Kv1 channels may be an early event in AD pathogenesis. Using murine Kv1.1 channels expressed in Xenopus oocytes, we have observed the effects of Aβ(1-42) and the “core” peptide (25-35) on both macro- and micro-scopic currents. Both the bath application of Aβ(1-42) and Aβ(25-35) produced 40-50% suppression of macroscopic Kv1.1 current within 30 m. Suppression of Kv1.1 by Aβ(1-42) was partially dependent on intracellular Ca2+ and PP2B, showing only ∼25% reduction when cells were loaded with BAPTA-AM or exposed to the PP2B-inhibitor cyclosporine A (CsA). Patch-clamp results suggested that Aβ-suppression of Kv1.1 involved both PP2B-dephosphorylation and direct protein-protein interaction of Aβ with Kv1.1. Exposure of the intracellular face of Kv1.1 channels in ripped-off oocyte patches to either catalytically-active PP2B, or Aβ(1-42), produced gradual reductions in p(open), followed by the abrupt disappearance of Kv1.1 activity. Using “tip-dip” artificial membrane methods, Aβ(25-35) exposure eliminated Kv1.1 channel activity when applied to the channel intracellular face. Kv1.1 channels have also been incorporated into Black Lipid Membranes (BLMs), and we are currently assessing the effects of exposure of Aβ to both intra- and extra-cellular faces of Kv1.1. Suppression of presynaptic Kv1.1 (and related) channels could lead to enhanced action potentials, thus allowing greater influx of Ca2+ and subsequent increase in glutamate release. Postsynaptically, the increased glutamate release, through activation of AMPA and NMDA receptors, may contribute to excitotoxicity.

Amyloid β perturbs elevated heme flux induced with neuronal development

IntroductionHeme is a central molecule in mitochondrial respiration and ATP generation in neuronal cells. Thus, we assessed the importance of altered heme metabolism in Alzheimer's disease (AD) pathogenesis. MethodsTo investigate the role of altered heme metabolism in AD, we identified heme-related proteins whose expression is altered in AD patients and mouse models exhibiting amyloid pathology. We detected the levels of proteins involved in heme synthesis, uptake, degradation, and function during neuronal differentiation and characterized the effects of Aβ. ResultsWe found that the expression levels of the rate-limiting heme synthetic enzyme ALAS1 and heme degradation enzyme HO-2 are selectively decreased in AD patients and mice. Aβ selectively reduces the levels of HO-2 and heme degradation, which are elevated to support neuronal functions in fully differentiated neuronal cells. DiscussionOur data show that lowered heme metabolism, particularly the decreased levels of heme degradation and HO-2, is likely a very early event in AD pathogenesis.

Behavioral and Neuropsychiatric Disorders in Alzheimer's Disease.

Alzheimer's disease (AD) is the most frequent type of dementia in the elderly, severely affecting functional and executive skills of subjects suffering from this disease. Moreover, the distress of caregivers as well as the social implications constitute a critical issue for families. Furthermore, cognitive impairment, along with behavioral disorders and neuropsychiatric symptoms are characteristics of AD. Although these are present with variations in prevalence, intensity, and progression, an important core of them is visible before cognitive impairment, especially depression and apathy, which affect at least 50% of patients. The most updated literature shows that depression and/or behavioral and neuropsychiatric symptoms (BNS) are part of the initial phase of the disease rather than just a risk factor. Thus, mood disorders are associated with anomalies in specific brain regions that disturb the normal balance of neurotransmission. This in turn is linked with an inflammatory pathway that leads to microglial activation and aggregated neurofibrillary tangle formation, finally triggering neuronal loss, according to our neuroimmunomodulation theory. Altogether, inflammation and tau aggregation are observed in preclinical stages, preceding the BNS of patients, which in turn are exhibited earlier than cognitive and functional impairment detected in AD. This review is focused on the latest insights of cellular and molecular processes associated with BNS in asymptomatic early-onset stages of AD. An important medical research focus is to improve quality of life of patients, through prevention and treatments of AD, and the study of behavioral disorders and early event in AD pathogenesis has a major impact.

Enhanced tau pathology via RanBP9 and Hsp90/Hsc70 chaperone complexes.

Accumulation of amyloid β (Aβ) and tau represent the two major pathological hallmarks of Alzheimer's disease (AD). Despite the critical importance of Aβ accumulation as an early event in AD pathogenesis, multiple lines of evidence indicate that tau is required to mediate Aβ-induced neurotoxic signals in neurons. We have previously shown that the scaffolding protein Ran-binding protein 9 (RanBP9), which is highly elevated in brains of AD and AD mouse models, both enhances Aβ production and mediates Aβ-induced neurotoxicity. However, it is unknown whether and how RanBP9 transmits Aβ-induced neurotoxic signals to tau. Here we show for the first time that overexpression or knockdown of RanBP9 directly enhances and reduces tau levels, respectively, in vitro and in vivo. Such changes in tau levels are associated with the ability of RanBP9 to physically interact with tau and heat shock protein 90/heat shock cognate 70 (Hsp90/Hsc70) complexes. Meanwhile, both RanBP9 and tau levels are simultaneously reduced by Hsp90 or Hsc70 inhibitors, whereas overexpression or knockdown of RanBP9 significantly diminishes the anti-tau potency of Hsp90/Hsc70 inhibitors as well as Hsc70 variants (WT & E175S). Further, RanBP9 increases the capacity for Hsp90 and Hsc70 complexes to bind ATP and enhances their ATPase activities in vitro. These observations in vitro and cell lines are recapitulated in primary neurons and in vivo, as genetic reduction in RanBP9 not only ameliorates tauopathy in Tau-P301S mice but also rescues the deficits in synaptic integrity and plasticity.

Elevated plasma ferritin in elderly individuals with high neocortical amyloid-β load.

Ferritin, an iron storage and regulation protein, has been associated with Alzheimer's disease (AD); however, it has not been investigated in preclinical AD, detected by neocortical amyloid-β load (NAL), before cognitive impairment. Cross-sectional analyses were carried out for plasma and serum ferritin in participants in the Kerr Anglican Retirement Village Initiative in Aging Health cohort. Subjects were aged 65-90 years and were categorized into high and low NAL groups via positron emission tomography using a standard uptake value ratio cutoff=1.35. Ferritin was significantly elevated in participants with high NAL compared with those with low NAL, adjusted for covariates age, sex, apolipoprotein E ɛ4 carriage and levels of C-reactive protein (an inflammation marker). Ferritin was also observed to correlate positively with NAL. A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve (AUC)=0.766), but was outperformed when plasma ferritin was added to the base model (AUC=0.810), such that at 75% sensitivity, the specificity increased from 62 to 71% on adding ferritin to the base model, indicating that ferritin is a statistically significant additional predictor of NAL over and above the base model. However, ferritin's contribution alone is relatively minor compared with the base model. The current findings suggest that impaired iron mobilization is an early event in AD pathogenesis. Observations from the present study highlight ferritin's potential to contribute to a blood biomarker panel for preclinical AD.

Energy crisis precedes global metabolic failure in a novel Caenorhabditis elegans Alzheimer Disease model.

Alzheimer Disease (AD) is a progressive neurological disorder characterized by the deposition of amyloid beta (Aβ), predominantly the Aβ1–42 form, in the brain. Mitochondrial dysfunction and impaired energy metabolism are important components of AD pathogenesis. However, the causal and temporal relationships between them and AD pathology remain unclear. Using a novel C. elegans AD strain with constitutive neuronal Aβ1–42 expression that displays neuromuscular defects and age-dependent behavioural dysfunction reminiscent of AD, we have shown that mitochondrial bioenergetic deficit is an early event in AD pathogenesis, preceding dysfunction of mitochondrial electron transfer chain (ETC) complexes and the onset of global metabolic failure. These results are consistent with an emerging view that AD may be a metabolic neurodegenerative disease, and also confirm that Aβ-driven metabolic and mitochondrial effects can be reproduced in organisms separated by large evolutionary distances.

Meta-analysis of synaptic pathology in Alzheimer's disease reveals selective molecular vesicular machinery vulnerability

IntroductionLoss of synapses best correlates to cognitive deficits in Alzheimer's disease (AD) in which oligomeric neurotoxic species of amyloid-β appears to contribute synaptic pathology. Although a number of clinical pathologic studies have been performed with limited sample size, there are no systematic studies encompassing large samples. Therefore, we performed a meta-analysis study. MethodsWe identified 417 publications reporting postmortem synapse and synaptic marker loss from AD patients. Two meta-analyses were performed using a single database of subselected publications and calculating the standard mean differences. ResultsMeta-analysis confirmed synaptic loss in selected brain regions is an early event in AD pathogenesis. The second meta-analysis of 57 synaptic markers revealed that presynaptic makers were affected more than postsynaptic markers. DiscussionThe present meta-analysis study showed a consistent synaptic loss across brain regions and that molecular machinery including endosomal pathways, vesicular assembly mechanisms, glutamate receptors, and axonal transport are often affected.

Cdk5-Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models.

Deregulated Cdk5 causes neurotoxic amyloid beta peptide (Aβ) processing and cell death, two hallmarks of Alzheimer's disease, through the Foxo3 transcriptional factor in hippocampal cells, primary neurons and an Alzheimer's disease mouse model. Using an innovative chemical genetic screen, we identified Foxo3 as a direct substrate of Cdk5 in brain lysates. Cdk5 directly phosphorylates Foxo3, which increased its levels and nuclear translocation. Nuclear Foxo3 initially rescued cells from ensuing oxidative stress by upregulating MnSOD (also known as SOD2). However, following prolonged exposure, Foxo3 upregulated Bim (also known as BCL2L11) and FasL (also known as FASLG) causing cell death. Active Foxo3 also increased Aβ(1-42) levels in a phosphorylation-dependent manner. These events were completely inhibited either by expressing phosphorylation-resistant Foxo3 or by depleting Cdk5 or Foxo3, highlighting a key role for Cdk5 in regulating Foxo3. These results were confirmed in an Alzheimer's disease mouse model, which exhibited increased levels and nuclear localization of Foxo3 in hippocampal neurons, which preceded neurodegeneration and Aβ plaque formation, indicating this phenomenon is an early event in Alzheimer's disease pathogenesis. Collectively, these results show that Cdk5-mediated phospho-regulation of Foxo3 can activate several genes that promote neuronal death and aberrant Aβ processing, thereby contributing to the progression of neurodegenerative pathologies.

Mitochondrial Toxic Effects of Aβ Through Mitofusins in the Early Pathogenesis of Alzheimer’s Disease

Mitochondrial dysfunction has been implicated in the pathogenesis of Alzheimer's disease (AD). However, it is obscure how amyloid-beta (Aβ) can impair mitochondria in the early stage of AD pathology. Using PrP-hAPP/hPS1 double-transgenic AD mouse model, we find that abnormal mitochondrial morphology and damaged mitochondrial structure in hippocampal neurons appear in the early stage of AD-like disease development. We also find consistent mitochondrial abnormalities in the SH-SY5Y cells, which express amyloid precursor protein (APP) Swedish mutation (APPsw) and have been used as a cell model of the early-onset AD. Significant changes of mitofusin GTPases (Mfn1 and Mfn2) were detected both in the PrP-hAPP/hPS1 brains and SH-SY5Y cells. Moreover, our results show that Aβ accumulation in neurons of PrP-hAPP/hPS1 mice can affect the neurogenesis prior to plaque formation. These findings suggest that mitochondrial impairment is a very early event in AD pathogenesis and abnormal expression of Mfn1 and Mfn2 caused by excessive intracellular Aβ is the possible molecular mechanism. Interestingly, L-theanine has significant effects on regulating mitochondrial fusion proteins in SH-SY5Y (APPsw) cells. Overall, our results not only suggest a new early mechanism of AD pathogenesis but also propose a preventive candidate, L-theanine, for the treatment of AD.

Tau oligomers and tau toxicity in neurodegenerative disease

AD (Alzheimer's disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of amyloid β-peptide and the intracellular accumulation of tau. Although there is much evidence linking tau to neurodegeneration, the precise mechanism of tau-mediated neurotoxicity remains elusive. The presence of tau-positive pre-tangle neurons lacking neurofibrillary tangles has been reported in AD brain tissue. In order to study this non-fibrillar tau, we generated a novel monoclonal antibody, named TOC1 (tau oligomeric complex 1), which selectively labels tau dimers and oligomers, but does not label filaments. Time-course analysis and antibody labelling indicates that oligomers appear as an early event in AD pathogenesis. Using a squid axoplasm assay, we have demonstrated that aggregated tau inhibits anterograde FAT (fast axonal transport), whereas monomeric tau has no effect. This inhibition requires a small stretch of N-terminal amino acids termed the PAD (phosphatase-activation domain). Using a PAD-specific antibody, TNT1 (tau N-terminal 1), we demonstrate that PAD exposure is increased in diseased neurons and this leads to an increase in FAT inhibition. Antibody co-labelling with the early-AD marker AT8 indicates that, similar to TOC1, TNT1 expression represents an early event in AD pathogenesis. Finally, the effects of the molecular chaperone Hsp70 (heat-shock protein 70) were also investigated within the squid axoplasm assay. We illustrate that Hsp70 preferentially binds to tau oligomers over filaments and prevents anterograde FAT inhibition observed with a mixture of both forms of aggregated tau. Together, these findings support the hypothesis that tau oligomers are the toxic form of tau in neurodegenerative disease.

CRMP2 Hyperphosphorylation is Characteristic of Alzheimer's Disease and not a Feature Common to Other Neurodegenerative Diseases

Collapsin response mediator protein 2 (CRMP2) is an abundant brain-enriched protein that regulates neurite outgrowth. It is phosphorylated by Cdk5 and GSK3, and these modifications are abnormally high in the brains of Alzheimer's disease (AD) patients. Increased phosphorylation of CRMP2 is also apparent in mouse models of AD that express mutated AβPP and PSEN1, but not AβPP or tau alone, where it is detectable before the appearance of amyloid plaques and neurofibrillary tangles, suggesting it is an early event in AD pathogenesis. Here, we have extended these observations by showing that CRMP2 is not hyperphosphorylated in mice overexpressing mutated PSEN1 alone, or in cultured neurons treated with soluble, oligomeric Aβ42 peptide. Similarly, CRMP2 phosphorylation was not increased in a mouse model of severe neurodegeneration (PMSC-1 knockout) or in cultured neurons subjected to neurotoxic concentrations of NMDA or staurosporine. Most interestingly, CRMP2 phosphorylation was not increased in frontal cortex from patients with frontotemporal lobar degeneration associated with mutations in MAPT or with Pick bodies. Together, these observations are consistent with the hypothesis that abnormal phosphorylation of CRMP2 is specific to AD and occurs downstream of excessive processing of AβPP, but that neither excessive Aβ42 peptide nor neurotoxicity alone are sufficient to promote hyperphosphorylation.

ZnT3 mRNA levels are reduced in Alzheimer's disease post-mortem brain

BackgroundZnT3 is a membrane Zn2+ transporter that is responsible for concentrating Zn2+ into neuronal presynaptic vesicles. Zn2+ homeostasis in the brain is relevant to Alzheimer's disease (AD) because Zn2+ released during neurotransmission may bind to Aβ peptides, accelerating the assembly of Aβ into oligomers which have been shown to impair synaptic function.ResultsWe quantified ZnT3 mRNA levels in Braak-staged human post mortem (pm) brain tissue from medial temporal gyrus, superior occipital gyrus, superior parietal gyrus, superior frontal gyrus and cerebellum from individuals with AD (n = 28), and matched controls (n = 5) using quantitative real-time PCR. ZnT3 mRNA levels were significantly decreased in all four cortical regions examined in the AD patients, to 45-60% of control levels. This reduction was already apparent at Braak stage 4 in most cortical regions examined. Quantification of neuronal and glial-specific markers in the same samples (neuron-specific enolase, NSE; and glial fibrillary acidic protein, GFAP) indicated that loss of cortical ZnT3 expression was more pronounced, and occurred prior to, significant loss of NSE expression in the tissue. Significant increases in cortical GFAP expression were apparent as the disease progressed. No gene expression changes were observed in the cerebellum, which is relatively spared of AD neuropathology.ConclusionsThis first study to quantify ZnT3 mRNA levels in human pm brain tissue from individuals with AD and controls has revealed a significant loss of ZnT3 expression in cortical regions, suggesting that neuronal cells in particular show reduced expression of ZnT3 mRNA in the disease. This suggests that altered neuronal Zn2+ handling may be an early event in AD pathogenesis.

A Novel Immunotherapy for Alzheimers Disease: Antibodies against the β-Secretase Cleavage Site of APP

One of the main neuropathological lesions observed at brain autopsy of Alzheimer's disease (AD) patients are the extracellular senile plaques mainly composed of amyloid-beta (Abeta) peptides. Abeta is generated by proteolytic processing of amyloid precursor protein (APP) via beta and gamma-secretases. The beta-secretase APP cleaving enzyme 1 (BACE1) has become a target of intense research aimed at blocking the enzyme activity. Recent studies showed that BACE1 is involved in processing other non-APP substrates, and that other proteases are involved in APP processing. We have recently established a novel approach to inhibit Abeta production via antibodies against the beta-secretase cleavage site of APP. These antibodies bind wild type and Swedish mutated APP expressed in transgenic mice brain tissues. The isolated antibodies do not bind any form of Abeta peptides. Antibody up-take experiments, using Chinese hamster ovary cells expressing wild-type APP, suggest that antibody internalization and trafficking are mediated via the endocytic pathway. Administration of antibodies to the cells growing media resulted in a considerable decrease in intracellular Abeta levels, as well as in the levels of the corresponding C-terminal fragment (C99). The relevance of intra-neuronal accumulation of mainly Abeta42 as an early event in AD pathogenesis suggests that this approach may be applicable as a novel therapeutic strategy in AD treatment.

Iron, copper, and iron regulatory protein 2 in Alzheimer's disease and related dementias

Accumulating evidence implicates a role for altered iron and copper metabolism in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). However, imbalances in the levels of the various forms of iron at different stages of AD have not been examined. In this pilot study we extracted and measured the levels of loosely bound, non-heme and total iron and copper in the frontal cortex and hippocampus of patients with mild–moderate AD ( n = 3), severe AD ( n = 8) and dementia with Lewy bodies (DLB, n = 6), using graphite furnace atomic absorption spectrometry (GFAAS). Additionally, the expression of iron regulatory protein 2 (IRP2) was examined in relation to the pathological hallmarks of AD and DLB, amyloid plaques, neurofibrillary tangles (NFT), and Lewy bodies, by immunohistochemistry. We found significantly decreased loosely bound iron in the hippocampal white matter of mild–moderate and severe AD patients and a trend towards increased non-heme iron in the hippocampal gray matter of severe AD patients. Furthermore, decreased levels of total copper were seen in severe AD and DLB frontal cortex compared to controls, suggesting an imbalance in brain metal levels in both AD and DLB. The decrease in loosely bound iron in mild–moderate AD patients may be associated with myelin breakdown seen in the beginning stages of AD and implicates that iron dysregulation is an early event in AD pathogenesis.

Intrathecal Chemokine Synthesis in Mild Cognitive Impairment and Alzheimer Disease

Immunoreactivity for several chemokines and for their related receptors has been demonstrated in resident cells of the central nervous system, and the up-regulation of some of them is associated with pathological changes found in Alzheimer disease (AD). To determine interferon-gamma-inducible protein 10 (IP-10), monocyte chemotactic protein 1 (MCP-1), and interleukin 8 (IL-8) levels in cerebrospinal fluid (CSF) from subjects with amnestic mild cognitive impairment (MCI) and patients with AD as compared with age-matched controls. Thirty-eight subjects with amnestic MCI, 36 patients with AD, and 41 age-matched subjects with noninflammatory affections of the nervous system. Evaluation of CSF chemokine production at time of diagnosis of MCI and AD; correlation with clinical and personal data. Longitudinal evaluation of subjects with MCI until conversion to AD. Cerebrospinal fluid IP-10 concentration was significantly increased in patients with MCI and mild AD but not in patients with severe AD (Mini-Mental State Examination score <15), whereas MCP-1 and IL-8 levels were increased in patients with MCI and all patients with AD. A significant positive correlation between Mini-Mental State Examination score and CSF IP-10 or MCP-1 concentration was observed in patients with AD. No correlation between IP-10 levels and age was found, whereas MCP-1 and IL-8 levels correlated positively with age. Out of 38 subjects with MCI, 19 developed AD within a 1- to 3-year follow-up. The presence of inflammatory molecules is likely to be a very early event in AD pathogenesis, even preceding the clinical onset of the disease, as demonstrated by subjects with MCI who developed AD over time. Interferon-gamma-inducible protein 10 is specifically increased in MCI and seems to decrease with the progression of AD, whereas MCP-1 and IL-8 are up-regulated also in late stages of the disease, suggesting a role in phases in which neurodegeneration is prevalent.

Serum MCP-1 levels are increased in mild cognitive impairment and mild Alzheimer's disease

Upregulation of a number of chemokines, including monocyte chemotactic protein-1 (MCP-1), is associated with Alzheimer's disease (AD) pathological changes. Emerging evidence suggests that inflammatory events precede the clinical development of AD, as cytokine disregulation has been observed also in patients with mild cognitive impairment (MCI). MCP-1 levels were evaluated in serum samples from 48 subjects with MCI, 94 AD patients and 24 age-matched controls. Significantly increased MCP-1 levels were found in MCI and mild AD, but not in severe AD patients as compared with controls. mRNA levels in peripheral blood mononuclear cells (PBMC), evaluated by quantitative RT-PCR analysis, paralleled serum MCP-1 levels. Moreover, a progressive MCP-1 decrease was observed over a 1-year follow up in a subgroup of MCI subjects converted to AD. MCP-1 upregulation is likely to be a very early event in AD pathogenesis, by far preceding the clinical onset of the disease. Nevertheless, as MCP-1 is likely to play a role in several pathologies with an inflammatory component, a possible usfulness as an early AD biomarker would be possible only in combination with other molecules.

Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer's disease

Multiple lines of evidence demonstrated that increased brain oxidative stress is a key feature of Alzheimer's disease (AD). Melatonin is a potent endogenous antioxidant and free radical scavenger. A transgenic mouse model for AD mimics the accumulation of senile plaques, neuronal loss, and memory impairment. Four-month-old transgenic mice were administrated melatonin at 10 mg/kg for 4 months. We investigated the long-term influence of melatonin on these mice before amyloid plaques were deposited. We found an increase in the levels of brain thiobarbituric acid-reactive substances (TBARS) and a decrease in glutathione (GSH) content, as well as accelerated upregulation of the apoptotic-related factors, such as Bax, caspase-3, and prostate apoptosis response-4 (Par-4) in transgenic mice, but not in wild-type (WT) littermates. Significantly, the increase in TBARS levels, reduction in superoxide dismutase activity, and GSH content were reinstated by melatonin. In addition, transgenic mice administered melatonin (10 mg/kg) showed a significant reduction in upregulated expression of Bax, caspase-3 and Par-4, indicating inhibited triggering of neuronal apoptosis. These results supported the hypothesis that oxidative stress was an early event in AD pathogenesis and that antioxidant therapy may be beneficial only if given at this stage of the disease process. In sharp contrast to conventional antioxidants, melatonin crosses the blood–brain barrier, is relatively devoid of toxicity, and constitutes a potential therapeutic candidate in AD treatment.