A molecular test for Alzheimer's disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimer's and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimer's disease 2-6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimer's disease.
One of the most important scientific discoveries of recent years was the disclosure that the intestinal microflora takes part in bidirectional communication between the gut and the brain. Scientists suggest that human gut microflora may even act as the "second brain" and be responsible for neurodegenerative disorders like Alzheimer's disease (AD). Although human-associated microbial communities are generally stable, they can be altered by common human actions and experiences. Enteric bacteria, commensal, and pathogenic microorganisms, may have a major impact on immune system, brain development, and behavior, as they are able to produce several neurotransmitters and neuromodulators like serotonin, kynurenine, catecholamine, etc., as well as amyloids. However, brain destructive mechanisms, that can lead to dementia and AD, start with the intestinal microbiome dysbiosis, development of local and systemic inflammation, and dysregulation of the gut-brain axis. Increased permeability of the gut epithelial barrier results in invasion of different bacteria, viruses, and their neuroactive products that support neuroinflammatory reactions in the brain. It seems that, inflammatory-infectious hypothesis of AD, with the great role of the gut microbiome, starts to gently push into the shadow the amyloid cascade hypothesis that has dominated for decades. It is strongly postulated that AD may begin in the gut, and is closely related to the imbalance of gut microbiota. This is promising area for therapeutic intervention. Modulation of gut microbiota through personalized diet or beneficial microbiota intervention, alter microbial partners and their products including amyloid protein, will probably become a new treatment for AD.
Inflammatory reactions could be both beneficial and detrimental to the brain, depending on strengths of their activation in various stages of neurodegeneration. Mild activation of microglia and astrocytes usually reveals neuroprotective effects and ameliorates early symptoms of neurodegeneration; for instance, released cytokines help maintain synaptic plasticity and modulate neuronal excitability, and stimulated toll-like receptors (TLRs) promote neurogenesis and neurite outgrowth. However, strong activation of glial cells gives rise to cytokine overexpression/dysregulation, which accelerates neurodegeneration. Altered mutual regulation of p53 protein, a major tumor suppressor, and NF-κB, the major regulator of inflammation, seems to be crucial for the shift from beneficial to detrimental effects of neuroinflammatory reactions in neurodegeneration. Therapeutic intervention in the p53-NF-κB axis and modulation of TLR activity are future challenges to cope with neurodegeneration.
Background: Inflammation is a part of the first line of defense of the body against invasive pathogens, and plays a crucial role in tissue regeneration and repair. A proper inflammatory response ensures the suitable resolution of inflammation and elimination of harmful stimuli, but when the inflammatory reactions are inappropriate it can lead to damage of the surrounding normal cells. The relationship between infections and Alzheimer’s Disease (AD) etiology, especially late-onset AD (LOAD) has been continuously debated over the past three decades.Methods: This review discusses whether infections could be a causative factor that promotes the progression of AD and summarizes recent investigations associating infectious agents and chronic inflammation with AD. Preventive and therapeutic approaches to AD in the context of an infectious etiology of the disease are also discussed.Results: Emerging evidence supports the hypothesis of the role of neurotropic viruses from the Herpesviridae family, especially Human herpesvirus 1 (HHV-1), Cytomegalovirus (CMV), and Human herpesvirus 2 (HHV-2), in AD neuropathology. Recent investigations also indicate the association between Hepatitis C virus (HCV) infection and dementia. Among bacteria special attention is focused on spirochetes family and on periodontal pathogens such as Porphyromonas gingivalis or Treponema denticola that could cause chronic periodontitis and possibly contribute to the clinical onset of AD.Conclusion: Chronic viral, bacterial and fungal infections might be causative factors for the inflammatory pathway in AD.
A number of distinct -amyloid (A) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural A-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic A and amyloidogenic non-A species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21-89 years. Antibody reactivity was most prominent against oligomeric assemblies of A and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of A1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant A, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from A toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with A the monkeys developed high titers not only against A peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of A antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD. A lzheimer's disease (AD) is the most common cause of dementia, affecting an estimated 5.3 million individuals in the United States alone. Deposits of -amyloid peptide (A) in extracellular plaques characterize the AD brain, but soluble oligomeric A species appear to be more neurotoxic than plaques and interfere with synaptic function (reviewed in ref. 1). Notably, most A peptides isolated from AD brains are posttranslationally modified and truncated (2-6), and some are proposed to be oxidized (7,8) or cross-linked at Tyr-10 (9). Although the pathogenic consequences of these modifications need to be resolved, most of them can stabilize A assemblies, interfere with proteolytic degradation, and increase A toxicity in vitro (7,8,10).One line of defense against toxic A species could be neutralizing antibodies. Stimulating the production of A antibodies by active immunization with synthetic A (11) or administering monoclonal A antibodies (12, 13) reduced amyloid pathology and inflammation and improved cognitive function in mouse models of AD (14). In patients with mild to moderate AD active immunization appears to reduce plaque load (15), and in some patients production of A antibodies correlated with attenuated cognitive decline (16). It has also been suggested that antibodies recognizing different domains (12,13,17) or conformations (18, 19) of A may have different efficacy in humans.Interestingly, antibodies agai...
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