Reduction of Amyloid Burden by Proliferated Homeostatic Microglia in Toxoplasma gondii-Infected Alzheimer's Disease Model Mice.

In this study, we confirmed that the number of resident homeostatic microglia increases during chronic Toxoplasma gondii infection. Given that the progression of Alzheimer's disease (AD) worsens with the accumulation of amyloid ß (Aß) plaques, which are eliminated through microglial phagocytosis, we hypothesized that T. gondii-induced microglial proliferation would reduce AD progression. Therefore, we investigated the association between microglial proliferation and Aß plaque burden using brain tissues isolated from 5XFAD AD mice (AD group) and T. gondii-infected AD mice (AD + Toxo group). In the AD + Toxo group, amyloid plaque burden significantly decreased compared with the AD group; conversely, homeostatic microglial proliferation, and number of plaque-associated microglia significantly increased. As most plaque-associated microglia shifted to the disease-associated microglia (DAM) phenotype in both AD and AD + Toxo groups and underwent apoptosis after the lysosomal degradation of phagocytosed Aß plaques, this indicates that a sustained supply of homeostatic microglia is required for alleviating Aß plaque burden. Thus, chronic T. gondii infection can induce microglial proliferation in the brains of mice with progressed AD; a sustained supply of homeostatic microglia is a promising prospect for AD treatment.

Human Neural Stem Cell Systems to Explore Pathogen-Related Neurodevelopmental and Neurodegenerative Disorders.

Building and functioning of the human brain requires the precise orchestration and execution of myriad molecular and cellular processes, across a multitude of cell types and over an extended period of time. Dysregulation of these processes affects structure and function of the brain and can lead to neurodevelopmental, neurological, or psychiatric disorders. Multiple environmental stimuli affect neural stem cells (NSCs) at several levels, thus impairing the normal human neurodevelopmental program. In this review article, we will delineate the main mechanisms of infection adopted by several neurotropic pathogens, and the selective NSC vulnerability. In particular, TORCH agents, i.e., Toxoplasma gondii, others (including Zika virus and Coxsackie virus), Rubella virus, Cytomegalovirus, and Herpes simplex virus, will be considered for their devastating effects on NSC self-renewal with the consequent neural progenitor depletion, the cellular substrate of microcephaly. Moreover, new evidence suggests that some of these agents may also affect the NSC progeny, producing long-term effects in the neuronal lineage. This is evident in the paradigmatic example of the neurodegeneration occurring in Alzheimer's disease.

Eupulcherol A, a triterpenoid with a new carbon skeleton from Euphorbia pulcherrima, and its anti-Alzheimer's disease bioactivity.

Eupulcherol A (1), a novel triterpenoid with an unprecedented carbon skeleton, was isolated from Euphorbia pulcherrima. Its structure was determined by comprehensive analysis of spectroscopic data, including HRESIMS and 1D and 2D NMR, and the absolute configuration was defined by single crystal X-ray diffraction analysis. Biological studies showed that compound 1 possessed anti-Alzheimer's disease (AD) bioactivity, which could delay paralysis of transgenic AD Caenorhabditis elegans. A plausible biogenetic pathway for eupulcherol A (1) was also proposed.

The Possibility of an Infectious Etiology of Alzheimer Disease.

Over the past three decades, there has been constant postulation regarding the infectious etiology of Alzheimer disease (AD), which in turn suggests the vital role of various infectious agents in AD-associated inflammatory pathways. Recent findings indicate anti-microbial properties of Aß, and suggest that Aß production and deposition in AD might be induced by infectious agents. Several types of spirochetes have been associated to dementia, cortical atrophy, and pathological and biological hallmarks of AD. A significant association between AD spirochetes and other pathogens like HSV-1 and Chlamydia pneumonia has now become well established. In neurons infected by HSV-1 showed Aß and hyperphosphorylated Tau accumulation. The expression of pro-inflammatory molecules have been found to be enhanced by specific bacterial ligands, and viral and bacterial DNA and RNA, thus activating the immune system. Aß has now been established as anti-microbial peptide capable of inducing pore formation, thus justifying their infection-mediated accumulation. Thus, a proper combination of anti-inflammatory, anti-viral, and antibiotic therapeutics might potentially prevent the progression of AD. Here, we discussed the potential role of bacterial, fungi, and viral infections in AD causation and progression, and the potential-associated therapies to counter the AD condition.

Toxoplasma gondii alters NMDAR signaling and induces signs of Alzheimer's disease in wild-type, C57BL/6 mice.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with cognitive decline and complete loss of basic functions. The ubiquitous apicomplexan parasite Toxoplasma gondii (T. gondii) infects up to one third of the world's population and is implicated in AD. METHODS: We infected C57BL/6 wild-type male and female mice with 10 T. gondii ME49 cysts and assessed whether infection led to behavioral and anatomical effects using immunohistochemistry, immunofluorescence, Western blotting, cell culture assays, as well as an array of mouse behavior tests. RESULTS: We show that T. gondii infection induced two major hallmarks of AD in the brains of C57BL/6 male and female mice: beta-amyloid (Aß) immunoreactivity and hyperphosphorylated Tau. Infected mice showed significant neuronal death, loss of N-methyl-D-aspartate receptor (NMDAR) expression, and loss of olfactory sensory neurons. T. gondii infection also caused anxiety-like behavior, altered recognition of social novelty, altered spatial memory, and reduced olfactory sensitivity. This last finding was exclusive to male mice, as infected females showed intact olfactory sensitivity. CONCLUSIONS: These results demonstrate that T. gondii can induce advanced signs of AD in wild-type mice and that it may induce AD in some individuals with underlying health problems.

Medium-chain plasma acylcarnitines, ketone levels, cognition, and gray matter volumes in healthy elderly, mildly cognitively impaired, or Alzheimer's disease subjects.

Aging, amyloid deposition, and tau-related pathology are key contributors to the onset and progression of Alzheimer's disease (AD). However, AD is also associated with brain hypometabolism and deficits of mitochondrial bioenergetics. Plasma acylcarnitines (ACCs) are indirect indices of altered fatty acid beta-oxidation, and ketogenesis has been found to be decreased on aging. Furthermore, in elderly subjects, alterations in plasma levels of specific ACCs have been suggested to predict conversion to mild cognitive impairment (MCI) or AD. In this study, we assayed plasma profiles of ACCs in a cohort of healthy elderly control, MCI subjects, and AD patients. Compared with healthy controls or MCI subjects, AD patients showed significant lower plasma levels of several medium-chain ACCs. Furthermore, in AD patients, these lower concentrations were associated with lower prefrontal gray matter volumes and the presence of cognitive impairment. Interestingly, lower levels of medium-chain ACCs were also found to be associated with lower plasma levels of 2-hydroxybutyric acid. Overall, these findings suggest that altered metabolism of medium-chain ACCs and impaired ketogenesis can be metabolic features of AD.

Why as a medicinal chemist I am not optimistic about the possibility of finding, in a reasonable timeframe, small-molecule drugs capable of curing the evolution of Alzheimer's disease.

Herein I explain why I feel that new and effective Alzheimer's disease (AD) drugs cannot emerge from current developed concepts such as the amyloid pathway, or acetylcholinesterase inhibitors. The discovery of new therapeutic approaches first requires an understanding of the intimate structure of brain matter, where memory and cognition are located, and how aging alters its structure and function. Only by joining the expertise of quantum physicists and physical chemists with that of medicinal chemists, pharmacologists, biologists and medical doctors can new AD research orientations emerge.

Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria.

It is established that chronic spirochetal infection can cause slowly progressive dementia, brain atrophy and amyloid deposition in late neurosyphilis. Recently it has been suggested that various types of spirochetes, in an analogous way to Treponema pallidum, could cause dementia and may be involved in the pathogenesis of Alzheimer's disease (AD). Here, we review all data available in the literature on the detection of spirochetes in AD and critically analyze the association and causal relationship between spirochetes and AD following established criteria of Koch and Hill. The results show a statistically significant association between spirochetes and AD (P = 1.5 × 10-17, OR = 20, 95% CI = 8-60, N = 247). When neutral techniques recognizing all types of spirochetes were used, or the highly prevalent periodontal pathogen Treponemas were analyzed, spirochetes were observed in the brain in more than 90% of AD cases. Borrelia burgdorferi was detected in the brain in 25.3% of AD cases analyzed and was 13 times more frequent in AD compared to controls. Periodontal pathogen Treponemas (T. pectinovorum, T. amylovorum, T. lecithinolyticum, T. maltophilum, T. medium, T. socranskii) and Borrelia burgdorferi were detected using species specific PCR and antibodies. Importantly, co-infection with several spirochetes occurs in AD. The pathological and biological hallmarks of AD were reproduced in vitro by exposure of mammalian cells to spirochetes. The analysis of reviewed data following Koch's and Hill's postulates shows a probable causal relationship between neurospirochetosis and AD. Persisting inflammation and amyloid deposition initiated and sustained by chronic spirochetal infection form together with the various hypotheses suggested to play a role in the pathogenesis of AD a comprehensive entity. As suggested by Hill, once the probability of a causal relationship is established prompt action is needed. Support and attention should be given to this field of AD research. Spirochetal infection occurs years or decades before the manifestation of dementia. As adequate antibiotic and anti-inflammatory therapies are available, as in syphilis, one might prevent and eradicate dementia.

Could Toxoplasma gondii have any role in Alzheimer disease?

BACKGROUND: Alzheimer disease (AD), a chronic progressive neurodegenerative disorder, has a mainly unknown multifactorial etiology. Neuroinflammatory mechanisms might contribute to the cascade of events leading to neuronal degeneration. Central nervous system infections have been previously suggested as possible etiological agents in the development of sporadic AD. Toxoplasmosis can be associated with various neuropsychiatric disorders. In this study, we aimed to investigate the possible association between toxoplasma infection and AD. METHODS: This study evaluated the serum anti-Toxoplasma gondii IgG levels. It included an age-matched and sex-matched study and control groups that consisted of 34 patients with AD and 37 healthy individuals, respectively. There were no difference between the socio economic states of the patients and control subjects. serecm anti-I-gondi IgG levels were measured by using ELISA. RESULTS: According to the statistical analysis, there were no significant differences among the patients and the control participants with respect to age (68.05±15.98, 62.91±5.89 y, P=0.072; respectively) and sex. The seropositivity rate for anti-T. gondii IgG antibodies among AD patients and control groups were 44.1% and 24.3%, respectively, and there was significant difference between the serum anti-T. gondii IgG levels (P=0.005). CONCLUSIONS: Our findings suggest that toxoplasma infection may be involved in the pathogenetic mechanisms of AD. If confirmed, a positive correlation between toxoplasmosis and AD may lead to new approaches for the management of AD.

Current and future treatments for Alzheimer's disease.

There are currently >5 million people in the United States who have been diagnosed with Alzheimer's disease. That prevalence rate is expected to triple as the population ages. The health and economic burden due to Alzheimer's disease is a worldwide problem, with some of the greatest burden coming from the developing world as people live longer in those societies. Throughout the world, the projected growth of Alzheimer's disease is dramatic. This is a worldwide public health problem of the highest order, and there is a compelling need to develop new treatments and methods of earlier diagnosis need to slow the progression of the disease and lessen its impact.

Interrater reliability and accuracy in identifying ischemic strokes using computed tomography scans in people with dementia.

OBJECTIVES: To assess the reliability and interobserver agreement of stroke identification on neuroimaging in patients presenting with dementia. DESIGN: Comparison study between neurologists, radiology reports, and autopsy. SETTING: Dementia registry within a health maintenance organization. PARTICIPANTS: Dementia patients with computed tomography (CT) scans obtained near the time of diagnosis and postmortem neuropathological examinations (N=99). MEASUREMENTS: Three neurologists independently read CT scans for the presence and locations of strokes. Radiology reports from these scans were reviewed. The results from neurologists, radiologists, and autopsies were compared. RESULTS: The positive predictive value for CT-observed strokes compared with their presence on autopsy was 0.44 to 0.49, regardless of the specialty of the observer. Strokes were present at autopsy in 46 of 99 cases. Agreement between neurologists on the presence of strokes was fair to moderate (kappa=0.27-0.56). Less agreement was found between neurologists and radiologists (kappa=0.00-0.11). Results improved slightly when each case was evaluated as any stroke present versus no stroke on imaging (kappa=0.34-0.75) or for the presence of multiple strokes (kappa=0.17-0.69). CONCLUSION: There is only fair to moderate agreement between observers regarding the identification of strokes on CT scans in patients presenting with dementia. Furthermore, strokes identified on imaging were present on pathology only half the time.

Co-expression of beta-amyloid precursor protein (betaAPP) and apolipoprotein E in cell culture: analysis of betaAPP processing.

Apolipoprotein E (ApoE) is the major genetic risk factor for Alzheimer's disease (AD). The ApoE4 allele is associated with earlier disease onset and greater cerebral deposition of the amyloid beta peptide (Abeta), the major constituent of senile (amyloid) plaques. The molecular mechanism underlying these effects of ApoE4 remains unclear; ApoE alleles could have different influences on Abeta production, extracellular aggregation, or clearance. Because the missense mutations on chromosomes 14 and 21 that cause familial forms of AD appear to lead to increased secretion of Abeta, it is important to determine whether ApoE4 has a similar effect. Here, we have examined the effects of all three ApoE alleles on the processing of betaAPP and the secretion of Abeta in intact cells. We established neural (HS683 human glioma) and non-neural (Chinese hamster ovary) cell culture systems that constitutively secrete both ApoE and Abeta at concentrations like those in human cerebrospinal fluid. betaAPP metabolites, generated in the presence of each ApoE allele, were analysed and quantified by two methods: immunoprecipitation and phosphorimaging, and ELISA. We detected no consistent allele-specific effects of ApoE on betaAPP processing in either cell type. Our data suggest that the higher amyloid burden found in AD subjects expressing ApoE4 is not due to increased amyloidogenic processing of betaAPP, in contrast to findings in AD linked to chromosome 14 or 21. These co-expressing cell lines will be useful in the further search for the effects of ApoE on Abeta aggregation or clearance under physiologically relevant conditions.

Care of the patient with Alzheimer's disease living at home.

Although the majority of people with Alzheimer's disease and related disorders are cared for in the home for most of their illness, there are few resources available on a consistent basis for nursing interaction. Nurses employed in a variety of settings provide ongoing information and support for families and caregivers in order to provide well-informed care. Because of the complexity of symptom presentation and care, the use of a simple conceptual model can be a valuable aid, helping families to understand behavioral alterations. The evaluation of behaviors as stress related assists both families and caregivers in determining the cause and effect of activities and environment to assist in enhancing comfort and life quality for both.