Nitric Oxide as a Determinant of Human Longevity and Health Span.

The master molecular regulators and mechanisms determining longevity and health span include nitric oxide (NO) and superoxide anion radicals (SOR). L-arginine, the NO synthase (NOS) substrate, can restore a healthy ratio between the dangerous SOR and the protective NO radical to promote healthy aging. Antioxidant supplementation orchestrates protection against oxidative stress and damage-L-arginine and antioxidants such as vitamin C increase NO production and bioavailability. Uncoupling of NO generation with the appearance of SOR can be induced by asymmetric dimethylarginine (ADMA). L-arginine can displace ADMA from the site of NO formation if sufficient amounts of the amino acid are available. Antioxidants such as ascorbic acids can scavenge SOR and increase the bioavailability of NO. The topics of this review are the complex interactions of antioxidant agents with L-arginine, which determine NO bioactivity and protection against age-related degeneration.

Tryptophan in Nutrition and Health.

Tryptophan is a rate-limiting essential amino acid and a unique building block of peptides and proteins [...].

Indoles as essential mediators in the gut-brain axis. Their role in Alzheimer's disease.

Sporadic late-onset Alzheimer's disease (AD) is the most frequent cause of dementia associated with aging. Due to the progressive aging of the population, AD is becoming a healthcare burden of unprecedented proportions. Twenty years ago, it was reported that some indole molecules produced by the gut microbiota possess essential biological activities, including neuroprotection and antioxidant properties. Since then, research has cemented additional characteristics of these substances, including anti-inflammatory, immunoregulatory, and amyloid anti-aggregation features. Herein, we summarize the evidence supporting an integrated hypothesis that some of these substances can influence the age of onset and progression of AD and are central to the symbiotic relationship between intestinal microbes and the brain. Studies have shown that some of these substances' activities result from interactions with biologically conserved pathways and with genetic risk factors for AD. By targeting multiple pathologic mechanisms simultaneously, certain indoles may be excellent candidates to ameliorate neurodegeneration. We propose that management of the microbiota to induce a higher production of neuroprotective indoles (e.g., indole propionic acid) will promote brain health during aging. This area of research represents a new therapeutic paradigm that could add functional years of life to individuals who would otherwise develop dementia.

Melatonin: Evolving Physiological Understanding and Potential Therapeutic Role in Pain Medicine Including Intervertebral Disc Degeneration.

BACKGROUND: Melatonin, one of the most versatile hormones in the body, is well appreciated in managing circadian rhythm and for antioxidant properties. Produced in the pineal gland and within mitochondria, melatonin influences many physiologic processes through receptor mediated and direct effects. OBJECTIVE: The present investigation explores the evolving pharmacologic properties of melatonin, as well as current therapeutic uses in areas where mitigating oxidative stress, inflammation, and cellular senescence. This review also delves into novel therapeutic potential of melatonin and how current research is revealing a wide array of therapeutic promise in pain medicine. STUDY DESIGN: A systematic review of randomized controlled trials (RCTs) and observational studies was performed using various search engines focused on melatonin and its role in pain medicine. METHODS: The available literature on melatonin and pain medicine was reviewed. A comprehensive literature search of multiple databases from 1966 to July 2024, including manual searches of the bibliography of known review articles was performed. Quality assessment of the included studies and best evidence synthesis were incorporated into qualitative and quantitative evidence synthesis. OUTCOME MEASURES: The primary outcome measure was the proportion of patients receiving melatonin with significant relief and functional improvement of greater than 50% of at least 3 months. Duration of relief was categorized as short-term (less than 6 months) and long-term (greater than 6 months). RESULTS: Melatonin can affect intervertebral disc (IVD) health through the enhancement of survival and function of nucleus pulposus cells, primarily through activation of the ERK1/2 signaling pathway. Melatonin also influences the biochemical environment of the IVD by modulating inflammation and oxidative stress, crucial factors in the pathogenesis of disc degeneration. Melatonin has been shown to reduce senescence and promote autophagy within disc cells, vital for clearing out damaged cellular components, preserving cellular function and preventing deterioration associated with aging and degenerative diseases. LIMITATIONS: Despite the availability of multiple studies, the paucity of clinical pain related literature is considered as the major drawback. CONCLUSION: Based on the present systematic review, melatonin plays a critical role in sleep, but evolving studies have demonstrated substantive roles in mitigating degenerative conditions in various tissues, including IVD degeneration. Ongoing studies will better clarify the role of melatonin as a potential therapeutic agent, including the targeted delivery to various body regions.

Major carboxyl terminal fragments generated by γ-secretase processing of the Alzheimer amyloid precursor are 50 and 51 amino acids long.

OBJECTIVES: To understand the cleavage of the amyloid ß protein (Aß) precursor (APP) by γ-secretase and to determine its changes in a representative familial Alzheimer disease (FAD) mutation. METHODS: Transfected cells expressing wild-type and FAD mutant APP were analyzed for changes in the levels of the major secreted Aß species and of the corresponding intracellular C-terminal APP fragments (APP intracellular domain, AICD) generated by γ-secretase, whereas radio-sequencing was used to precisely identify the resulting cleavage site(s). RESULTS: The AICD fragment(s) generated by γ-secretase cleavage comigrated in gels with a 50-residue synthetic peptide used as control, which is smaller than the 59 and 57 residues predicted from Aß ending at positions 40 (Aß40) and 42 (Aß42), respectively. In agreement with previous findings, an FAD mutant form of presenilin 1 (PS1-M139V) significantly increased the longer Aß42 while showing trends toward reducing Aß40. AICD levels were reduced by the mutation, suggesting that γ-secretase activity may be actually impaired by the mutation. Radiosequence analysis in cells expressing wild-type PS1 detected γ-secretase cleavage sites at the Aß peptide bond L(49)-V(50) to generate a 50-amino acid (aa) AICD fragment (AICD50) and the Aß peptide bond T(48)-L(49), generating an AICD of 51 aa (AICD51). No other cleavage sites were reliably detected. CONCLUSIONS: Based on findings that the FAD mutation that increases Aß42 also reduces AICD, we propose that γ-secretase activity is impaired by FAD mutations and predict that physiologic and environmental agents that inhibit γ-secretase will actually induce AD pathogenesis rather that prevent it. Furthermore, we propose that the cleavage site to generate AICD is naturally ragged and occurs predominantly at two sites 48 and 49 aa from the start of the Aß sequence. Thus, end specific antibodies to these two sites will need to be generated to study the quantitative relationships between these two cleavages in sporadic AD and FAD.

Changes of tRNA-Derived Fragments by Alzheimer's Disease in Cerebrospinal Fluid and Blood Serum.

BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, affecting individuals over 65. AD is also a multifactorial disease, with disease mechanisms incompletely characterized, and disease-modifying therapies are marginally effective. Biomarker signatures may shed light on the diagnosis, disease mechanisms, and the development of therapeutic targets. tRNA-derived RNA fragments (tRFs), a family of recently discovered small non-coding RNAs, have been found to be significantly enhanced in human AD hippocampus tissues. However, whether tRFs change in body fluids is unknown. OBJECTIVE: To investigate whether tRFs in body fluids are impacted by AD. METHODS: We first used T4 polynucleotide kinase-RNA-seq, a modified next-generation sequencing technique, to identify detectable tRFs in human cerebrospinal fluid and serum samples. The detectable tRFs were then compared in these fluids from control, AD, and mild cognitive impairment patients using tRF qRT-PCR. The stability of tRFs in serum was also investigated by checking the change in tRFs in response to protein digestion or exosome lysis. RESULTS: Among various tRFs, tRF5-ProAGG seemed to be impacted by AD in both cerebrospinal fluid and serum. AD-impacted serum tRF5-ProAGG showed a correlation with the AD stage. Putative targets of tRF5-ProAGG in the hippocampus were also predicted by a computational algorithm, with some targets being validated experimentally and one of them being in a negative correlation with tRF5-ProAGG even using a small size of samples. CONCLUSIONS: tRF5-ProAGG showed the potential as an AD biomarker and may play a role in disease progression.

Targets for AD treatment: conflicting messages from γ-secretase inhibitors.

Current evidence suggests that Alzheimer's disease (AD) is a multi-factorial disease that starts with accumulation of multiple proteins. We have previously proposed that inhibition of γ-secretase may impair membrane recycling causing neurodegeneration starting at synapses (Sambamurti K., Suram A., Venugopal C., Prakasam A., Zhou Y., Lahiri D. K. and Greig N. H. A partial failure of membrane protein turnover may cause Alzheimer's disease: a new hypothesis. Curr. Alzheimer Res., 3, 2006, 81). We also proposed familal AD mutations increase Aß42 by inhibiting γ-secretase. Herein, we discuss the failure of Eli Lilly's γ-secretase inhibitor, semagacestat, in clinical trials in the light of our hypothesis, which extends the problem beyond toxicity of Aß aggregates. We elaborate that γ-secretase inhibitors lead to accumulation of amyloid precursor protein C-terminal fragments that can later be processed by γ-secretase to yields bursts of Aß to facilitate aggregation. Although we do not exclude a role for toxic Aß aggregates, inhibition of γ-secretase can affect numerous substrates other than amyloid precursor protein to affect multiple pathways and the combined accumulation of multiple peptides in the membrane may impair its function and turnover. Taken together, protein processing and turnover pathways play an important role in maintaining cellular homeostasis and unless we clearly see consistent disease-related increase in their levels or activity, we need to focus on preserving their function rather than inhibiting them for treatment of AD and similar diseases.

Insulin Resistance is Associated with Central Pain in Patients with Fibromyalgia.

BACKGROUND: Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to insulin. IR has been associated with multiple conditions, including chronic pain. Fibromyalgia (FM) is one of the common generalized chronic painful conditions with an incidence rate affecting 3% to 6% of the population. Substantial interest and investigation into FM continue to generate  many hypotheses.The relationship between IR and FM has not been explored. IR is known to cause abnormalities in the cerebral microvasculature, leading to focal hypoperfusion. IR also has been shown to cause cognitive impairment in FM patients, as in parkinsonism. As demonstrated by advanced imaging methods, similar brain perfusion abnormalities occur in the brain of patients with FM as with IR. OBJECTIVES: To determine the potential association between FM and IR. SETTING: Subspecialty pain medicine clinics. STUDY DESIGN: Observational cross-sectional study. METHODS: Laboratory data was extracted through a retrospective review of medical records from patients who had met the American College of Rheumatology (ACR) criteria for FM. The Hemoglobin A1c (HbA1c) values from 33 patients with FM were compared with the means of the glycated HbA1c levels of 2 control populations. In addition, established indices of IR [Quantitative Insulin Sensitivity Check Index (QUICKI) and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)] were calculated in a subgroup of patients in whom the analytes necessary for these calculations were available. To assess for confounding factors, the associations between HbA1c, QUICKI, HOMA-IR, fasting insulin levels, and glucose, after controlling for age, were explored by multiple analyses of variance with relation to gender and ethnicity. RESULTS: We found an association between IR and FM that was independent of age, gender, and ethnicity. We found that patients with FM belong to a distinct population that can be segregated from the control groups by their HbA1c levels, a surrogate marker of IR. This was demonstrated by analyzing the data after introducing an age correction into a linear regression model. This strategy showed significant differences between patients with FM and control subjects (P < 0.0001 and P  = 0.0002, for 2 separate control populations, respectively). A subgroup analysis using the QUICKI and HOMA-IR showed that all patients with FM in this subgroup (100%) exhibited laboratory abnormalities pointing to IR. LIMITATIONS: Small observational cross-sectional study. There are also intrinsic limitations that are attributed to cross-sectional studies. CONCLUSION: The association demonstrated in this study warrant further investigation, including the pursuit of randomized, double-blind clinical trials to determine the effect of improving insulin sensitivity in FM related pain scores. Such studies could unveil a potential pathogenetic relationship between FM, central pain, and IR. Based on these initial findings, we present the hypothesis that IR may underlie pathological mechanisms leading to central pain. If confirmed, this may lead to a paradigm shift in the management of central pain.

Methodology for Evidence Synthesis and Development of Comprehensive Evidence-Based Guidelines for Interventional Techniques in Chronic Spinal Pain.

BACKGROUND: The re-engineered definition of clinical guidelines in 2011 from the IOM (Institute of Medicine) states, "clinical practice guidelines are statements that include recommendations intended to optimize patient care that is informed by a systematic review of evidence and an assessment of the benefit and harms of alternative care options." The revised definition distinguishes between the term "clinical practice guideline" and other forms of clinical guidance derived from widely disparate development processes, such as consensus statements, expert advice, and appropriate use criteria. OBJECTIVE: To assess the literature and develop methodology for evidence synthesis and development of comprehensive evidence-based guidelines for interventional techniques in chronic spinal pain. METHODS: A systematic review of the literature including methodology of guideline development encompassing GRADE approach for guidance on evidence synthesis with recommendations. RESULTS: Some of the many factors described in 2011 continue as of 2020 and impede the development of clinical practice guidelines. These impediments include biases due to a variety of conflicts and confluence of interest, inappropriate and poor methodological quality, poor writing and ambiguous presentation, projecting a view that these are not applicable to individual patients or too restrictive with the elimination of clinician autonomy, and overzealous and inappropriate recommendations, either positive, negative, or non-committal. Thus, ideally, a knowledgeable, multidisciplinary panel of experts with true lack of bias and confluence of interest must develop guidelines based on a systematic review of the existing evidence. This manuscript describes evidence synthesis from observational studies, various types of randomized controlled trials (RCTs), and, finally, methodological and reporting quality of systematic reviews. The manuscript also describes various methods utilized in the assessment of the quality of observational studies, diagnostic accuracy studies, RCTs, and systematic reviews. LIMITATIONS: Paucity of publications with appropriate evidence synthesis methodology in reference to interventional techniques. CONCLUSION: This review described comprehensive evidence synthesis derived from systematic reviews, including methodologic quality and bias measurement. The manuscript described various methods utilized in the assessment of the quality of the systematic reviews, RCTs, diagnostic accuracy studies, and observational studies.

Leptin and the skin: a new frontier.

Here, we examine the currently available information which supports that the adipokine, leptin, is a major player in the biology and pathology of mammalian skin and its appendages. Specifically, the potent metabolic effects of leptin and its mimetics may be utilized to improve, preserve and restore skin regeneration and hair cycle progression, and may halt or even partially reverse some aspects of skin ageing. Since leptin can enhance mitochondrial activity and biogenesis, this may contribute to the wound healing-promoting and hair growth-modulatory effects of leptin. Leptin dependent intracellular signalling by the Janus kinase 2 dependent signal transducer and activator of transcription 3, adenosine monophosphate kinase, and peroxisome proliferator-activated receptor (PPAR) gamma coactivator/PPAR converges to mediate mitochondrial metabolic activation and enhanced cell proliferation which may orchestrate the potent developmental, trophic and protective effects of leptin. Since leptin and leptin mimetics have already been clinically tested, investigative dermatology is well-advised to place greater emphasis on the systematic exploration of the cutaneous dimensions and dermatological potential of this pleiotropic hormone.

Is insulin resistance the cause of fibromyalgia? A preliminary report.

Fibromyalgia (FM) is one of the most frequent generalized pain disorders with poorly understood neurobiological mechanisms. This condition accounts for an enormous proportion of healthcare costs. Despite extensive research, the etiology of FM is unknown and thus, there is no disease modifying therapy available for this condition. We show that most (if not all) patients with FM belong to a distinct population that can be segregated from a control group by their glycated hemoglobin A1c (HbA1c) levels, a surrogate marker of insulin resistance (IR). This was demonstrated by analyzing the data after introducing an age stratification correction into a linear regression model. This strategy showed highly significant differences between FM patients and control subjects (p < 0.0001 and p = 0.0002, for two separate control populations, respectively). A subgroup of patients meeting criteria for pre-diabetes or diabetes (patients with HbA1c values of 5.7% or greater) who had undergone treatment with metformin showed dramatic improvements of their widespread myofascial pain, as shown by their scores using a pre and post-treatment numerical pain rating scale (NPRS) for evaluation. Although preliminary, these findings suggest a pathogenetic relationship between FM and IR, which may lead to a radical paradigm shift in the management of this disorder.

Do Regenerative Medicine Therapies Provide Long-Term Relief in Chronic Low Back Pain: A Systematic Review and Metaanalysis.

BACKGROUND: Several cell-based therapies have been proposed in recent years the management of low back pain, including the injection of medicinal signaling cells or mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP). However, there is only emerging clinical evidence to support their use at this time. OBJECTIVE: To assess the effectiveness of MSCs or PRP injections in the treatment of low back and lower extremity pain. STUDY DESIGN: A systematic review and metaanalysis of the effectiveness of PRP and MSCs injections in managing low back and lower extremity pain. DATA SOURCES: PubMed, Cochrane Library, US National Guideline Clearinghouse, prior systematic reviews, and reference lists. The literature search was performed from 1966 through June 2018. STUDY SELECTION: Randomized trials, observational studies, and case reports of injections of biologics into the disc, epidural space, facet joints, or sacroiliac joints. DATA EXTRACTION: Data extraction and methodological quality assessment were performed utilizing Cochrane review methodologic quality assessment and Interventional Pain Management Techniques - Quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB) and Interventional Pain Management Techniques - Quality Appraisal of Reliability and Risk of Bias Assessment for Nonrandomized Studies (IPM-QRBNR). The evidence was summarized utilizing principles of best evidence synthesis on a scale of 1 to 5. DATA SYNTHESIS: Twenty-one injection studies met inclusion criteria. There were 12 lumbar disc injections, 5 epidural, 3 lumbar facet joint, and 3 sacroiliac joint studies RESULTS: Evidence synthesis based on a single-arm metaanalysis, randomized controlled trials (RCTs), and observational studies, disc injections of PRP and MSCs showed Level 3 evidence (on a scale of Level I through V). Evidence for epidural injections based on single-arm metaanalysis, a single randomized controlled trial and other available studies demonstrated Level 4 (on a scale of Level I through V) evidence. Similarly, evidence for lumbar facet joint injections and sacroiliac joint injections without metaanalysis demonstrated Level 4 evidence (on a scale of Level I through V). LIMITATIONS: Lack of high quality RCTs. CONCLUSION: The findings of this systematic review and single-arm metaanalysis shows that MSCs and PRP may be effective in managing discogenic low back pain, radicular pain, facet joint pain, and sacroiliac joint pain, with variable levels of evidence in favor of these techniques. KEY WORDS: Chronic low back pain, regenerative therapy, medicinal signaling or mesenchymal stem cells, platelet-rich plasma, disc injection, lumbar facet joint injections, sacroiliac joint injections.

Luteinizing hormone modulates cognition and amyloid-beta deposition in Alzheimer APP transgenic mice.

Until recently, the study of hormonal influences in Alzheimer disease was limited to the role of sex steroids. Despite numerous epidemiological studies supporting a protective role for estrogen in Alzheimer disease, recent studies show that estrogen administration in elderly women increases the risk of disease. Reconciling these contradictory reports, we previously hypothesized that other hormones of the hypothalamic-pituitary-gonadal axis, such as luteinizing hormone, may be involved in the onset and development of the disease. In this regard, luteinizing hormone is elevated in Alzheimer disease and is known to modulate amyloidogenic processing of amyloid-beta protein precursor. Therefore, in this study, to evaluate the therapeutic potential of luteinizing hormone ablation, we administered a gonadotropin-releasing hormone analogue, leuprolide acetate, to an aged transgenic mouse model of Alzheimer disease (Tg 2576) and measured cognitive Y-maze performance and amyloid-beta deposition after 3 months of treatment. Our data indicate that luteinizing hormone ablation significantly attenuated cognitive decline and decreased amyloid-beta deposition as compared to placebo-treated animals. Importantly, leuprolide acetate-mediated reduction of amyloid-beta correlated with improved cognition. Since both cognitive loss and amyloid-beta deposition are features of Alzheimer disease, leuprolide acetate treatment may prove to be a useful therapeutic strategy for this disease.

Fine-tuning the amphiphilicity: a crucial parameter in the design of potent alpha-phenyl-N-tert-butylnitrone analogues.

A new series of hydrophilic, lipophilic, and amphiphilic alpha-phenyl-N-tert-butylnitrone (PBN) derivatives were synthesized to explore the relationship between their hydrophilic-lipophilic properties and antioxidant potency. Very potent protective effects of amphiphilic lactobionamide and tris(hydroxymethyl)aminomethane PBN derivatives were observed in mitochondrial preparations, in cell cultures, and in rotifers exposed to unspecific and mitochondria targeted oxidotoxins.

Fluorinated amphiphilic amino acid derivatives as antioxidant carriers: a new class of protective agents.

The use of classical antioxidants is limited by their low bioavailabilities, and therefore, high doses are usually required to display significant protective activity. In a recent article (J. Med. Chem. 2003, 46, 5230) we showed that the ability of the alpha-phenyl-N-tert-butylnitrone (PBN) to restore the viability of ATPase-deficient human skin fibroblasts was greatly enhanced by grafting it on a fluorinated amphiphilic carrier. With the aim of extending this concept to other antioxidants, we present here the design, the synthesis, and the physicochemical measurements of a new series of fluorinated amphiphilic antioxidant derivatives. The hydroxyl radical scavenging activity and the radical reducing potency of these newly designed compounds were respectively demonstrated in an ABTS competition and an ABTS(*+) reduction assay. We also showed that the protective effects of amphiphilic antioxidants derived from PBN, Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) or lipoic acid (5-[1,2]-dithiolan-3-ylpentanoic acid) in primary cortical mixed cell cultures exposed to oxidotoxins are greatly improved compared to their parent compounds in the following rank-order: (1) PBN, (2) Trolox, and (3) lipoic acid. In contrast, the protective activity of indole-3-propionic acid was slightly decreased by grafting it on the amphiphilic carrier. Similar observations were made in in vivo experiments using aquatic invertebrate microorganisms, called rotifers, which were exposed to lethal concentrations of nonselective (H(2)O(2)) and mitochondria-selective (doxorubicin) oxidotoxins. The conclusion of these studies is that fluorinated amphiphilic PBN, Trolox, and lipoic acid derivatives exhibit very potent protective activities in in vitro and in vivo experiments. The findings demonstrated herein therefore strongly suggest that the amphiphilic character enhances the bioavailability of the antioxidants and allows for a selective targeting of mitochondria.

Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer's disease.

Amyloid-ß proteins (Aß) of 42 (Aß42) and 40 aa (Aß40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer's disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aß precursor protein (APP), Presenilin-1 (PS1), Presenilin- 2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E (ApoE-ε4) foster the accumulation of Aß and also induce the entire spectrum of pathology associated with the disease. Aß accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by ß-site APP cleaving enzyme (BACE1) and γ-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aß. Although Aß accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aß production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aß42 or both Aß40 and Aß42. However, the vast majority of AD patients accumulate Aß without these known mutations. This led to proposals that impairment of Aß degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aß and we have recently established that the mechanism is by skirting Aß degradation. This review outlines major cellular pathways of Aß degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Aß turnover.

Cholesterol, oxidative stress, and Alzheimer's disease: expanding the horizons of pathogenesis.

Recent epidemiological, clinical, and experimental data suggest that cholesterol may play a role in Alzheimer's disease (AD). We have recently shown that cholesterolemia has a profound effect in the development and modulation of amyloid pathology in a transgenic model of AD. This review summarizes recent advancements in our understanding of the potential role of cholesterol and the amyloid beta protein in initiating the generation of free radicals and points out their role in a chain of events that causes damage of essential macromolecules in the central nervous system and culminates in neuronal dysfunction and loss. Experimental data links cholesterol and oxidative stress with some neurodegenerative aspects of AD.

Deficiency of chaperonin 60 in Down's syndrome.

Patients with Down syndrome (DS) and Alzheimer's disease (AD) share a number of characteristic neuropathologic lesions. Several lines of evidence suggest that mitochondria and the oxidative stress response are involved in the pathogenesis of both conditions. In the process of investigating the stress response in DS, we discovered a defective basal expression of a major mitochondrial heat shock protein, chaperonin 60 (Cpn60) in non-transformed dermal fibroblast cell lines from DS individuals. Such a defect was not present in control cells that had been cultured under identical physiological growth conditions. A quantitative analysis by Western blots showed a marked reduction of Cpn60 per equal amount of total protein in DS cells to an average of 35% of normal. Northern blot studies confirmed the defect and also showed a marked reduction of the mRNA signal for Cpn60 in all the DS cell lines. To gain further information, experiments were conducted to study the rate of de-novo synthesis of Cpn60 at normal and supraoptimal temperatures in DS and controls. Results showed no significant differences between the two study groups. HSP60 is important in mitochondrial function and defects in these organelles have been reported in DS and AD. Thus, the findings may have potential implications in the neuropathology of DS.