Autism genes and the leukocyte transcriptome in autistic toddlers relate to pathogen interactomes, infection and the immune system. A role for excess neurotrophic sAPPα and reduced antimicrobial Aβ - ScienceDirect

Prenatal and early childhood infections have been implicated in autism.
Many autism susceptibility genes (206 Autworks genes) are localised in
the immune system and are related to immune/infection pathways. They are
enriched in the host/pathogen interactomes of 18 separate microbes
(bacteria/viruses and fungi) and to the genes regulated by bacterial
toxins, mycotoxins and Toll-like receptor ligands. This enrichment was
also observed for misregulated genes from a microarray study of
leukocytes from autistic toddlers. The upregulated genes from this
leukocyte study also matched the expression profiles in response to
numerous infectious agents from the Broad Institute molecular signatures
database. They also matched genes related to sudden infant death
syndrome and autism comorbid conditions (autoimmune disease, systemic
lupus erythematosus, diabetes, epilepsy and cardiomyopathy) as well as
to estrogen and thyrotropin responses and to those upregulated by
different types of stressors including oxidative stress, hypoxia,
endoplasmic reticulum stress, ultraviolet radiation or
2,4-dinitrofluorobenzene, a hapten used to develop allergic skin
reactions in animal models. The oxidative/integrated stress response is
also upregulated in the autism brain and may contribute to myelination
problems. There was also a marked similarity between the expression
signatures of autism and Alzheimer's disease, and 44 shared
autism/Alzheimer's disease genes are almost exclusively expressed in the
blood-brain barrier. However, in contrast to Alzheimer's disease,
levels of the antimicrobial peptide beta-amyloid are decreased and the
levels of the neurotrophic/myelinotrophic soluble APP alpha are
increased in autism, together with an increased activity of α-secretase.
sAPPα induces an increase in glutamatergic and a decrease in GABA-ergic
synapses creating and excitatory/inhibitory imbalance that has also
been observed in autism. A literature survey showed that multiple autism
genes converge on APP processing and that many are able to increase
sAPPalpha at the expense of beta-amyloid production. A genetically
programmed tilt of this axis towards an overproduction of
neurotrophic/gliotrophic sAPPalpha and underproduction of antimicrobial
beta-amyloid may explain the brain overgrowth and myelination
dysfunction, as well as the involvement of pathogens in autism.

Microglia and amyloid precursor protein coordinate control of transient Candida cerebritis with memory deficits | Nature Communications

Bloodborne infections with Candida albicans are an increasingly
recognized complication of modern medicine. Here, we present a mouse
model of low-grade candidemia to determine the effect of disseminated
infection on cerebral function and relevant immune determinants. We show
that intravenous injection of 25,000 C. albicans cells causes a
highly localized cerebritis marked by the accumulation of activated
microglial and astroglial cells around yeast aggregates, forming
fungal-induced glial granulomas. Amyloid precursor protein accumulates
within the periphery of these granulomas, while cleaved amyloid beta
(Aβ) peptides accumulate around the yeast cells. CNS-localized C. albicans
further activate the transcription factor NF-κB and induce production
of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor (TNF), and Aβ
peptides enhance both phagocytic and antifungal activity from BV-2
cells. Mice infected with C. albicans display mild memory
impairment that resolves with fungal clearance. Our results warrant
additional studies to understand the effect of chronic cerebritis on
cognitive and immune function.

Reaction of Amyloid-β Peptide Antibody with Different Infectious Agents Involved in Alzheimer’s Disease - IOS Press

As early as the 1980s, molecular virologist Ruth Itzhaki began to
investigate if there was a causal connection between infections and
neurodegenerative disorder. Although the theory has yet to be
universally embraced, in 2016 Itzhaki and 33 other scientists from all
over the world published a review
article in this very journal presenting evidence for the causal role of
pathogens in Alzheimer’s disease (AD). Exactly how and in what way
pathogens affect the induction of AD has yet to be determined, but one
possible answer may involve the cross-reactivity of different pathogens
with amyloid-β (Aβ). Aβ autoantibodies have been detected in the serum
and cerebrospinal fluid of AD patients and in some healthy individuals.
In the present study our major goal was to investigate whether
antibodies made against Aβ would react both with other brain proteins as
well as pathogens associated with AD as a result of molecular mimicry
or the binding of bacterial toxins to Aβ42. Our study used a specific
monoclonal antibody made against Aβ42, which not only reacted strongly
with Aβ42, tau protein, and α-synuclein, but also had from weak to
strong reactions with 25 different pathogens or their molecules, some of
which have been associated with AD. The homology between peptide
stretches of microbial origin and proteins involved in AD could be a
mechanism by which antibodies to homologous peptides mount attacks
against autoantigens in AD. We concluded that bacterial molecules bind
to Aβ protein, forming small oligomers, then encasing pathogens and
their molecules to form amyloid plaques, the tell-tale markers of AD.
Conversely, these same Aβ peptides induce the production of antibodies
to both Aβ42 and bacterial molecules, which may inhibit bacterial
pathogenesis, but in the process may promote amyloid plaque formation.

Translational Psychiatry - Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models

 Exposure to particulate matter (PM) in the ambient air and its interactions with APOE alleles may contribute to the acceleration of brain aging and the pathogenesis of Alzheimer’s disease (AD). Neurodegenerative effects of particulate air pollutants were examined in a US-wide cohort of older women from the Women’s Health Initiative Memory Study (WHIMS) and in experimental mouse models. Residing in places with fine PM exceeding EPA standards increased the risks for global cognitive decline and all-cause dementia respectively by 81 and 92%, with stronger adverse effects in APOE ε4/4 carriers. Female EFAD transgenic mice (5xFAD+/−/human APOE ε3 or ε4+/+) with 225 h exposure to urban nanosized PM (nPM) over 15 weeks showed increased cerebral β-amyloid by thioflavin S for fibrillary amyloid and by immunocytochemistry for Aβ deposits, both exacerbated by APOE ε4. Moreover, nPM exposure increased Aβ oligomers, caused selective atrophy of hippocampal CA1 neurites, and decreased the glutamate GluR1 subunit. Wildtype C57BL/6 female mice also showed nPM-induced CA1 atrophy and GluR1 decrease. In vitro nPM exposure of neuroblastoma cells (N2a-APP/swe) increased the pro-amyloidogenic processing of the amyloid precursor protein (APP). We suggest that airborne PM exposure promotes pathological brain aging in older women, with potentially a greater impact in ε4 carriers. The underlying mechanisms may involve increased cerebral Aβ production and selective changes in hippocampal CA1 neurons and glutamate receptor subunits.

Glaucoma drug brimonidine may have potential to treat Alzheimer's disease

In trials on rats, the drug brimonidine, which is routinely used to lower eye pressure in glaucoma patients, has been found to reduce the formation of amyloid proteins in the retina, which are believed to be linked to Alzheimer's. The research was reported in the journal Cell Death and Disease.


Here's the paper:-

Non-amyloidogenic effects of α2 adrenergic agonists: implications for brimonidine-mediated neuroprotection.

The amyloid beta (Aβ) pathway is strongly implicated in neurodegenerative conditions such as Alzheimer's disease and more recently, glaucoma. Here, we identify the α2 adrenergic receptor agonists (α2ARA) used to lower intraocular pressure can prevent retinal ganglion cell (RGC) death via the non-amyloidogenic Aβ-pathway. Neuroprotective effects were confirmed in vivo and in vitro in different glaucoma-related models using α2ARAs brimonidine (BMD), clonidine (Clo) and dexmedetomidine. α2ARA treatment significantly reduced RGC apoptosis in experimental-glaucoma models by 97.7% and 92.8% (BMD, P<0.01) and 98% and 92.3% (Clo, P<0.01)) at 3 and 8 weeks, respectively. A reduction was seen in an experimental Aβ-induced neurotoxicity model (67% BMD and 88.6% Clo, both P<0.01, respectively), and in vitro, where α2ARAs significantly (P<0.05) prevented cell death, under both hypoxic (CoCl2) and stress (UV) conditions. In experimental-glaucoma, BMD induced ninefold and 25-fold and 36-fold and fourfold reductions in Aβ and amyloid precursor protein (APP) levels at 3 and 8 weeks, respectively, in the RGC layer, with similar results with Clo, and in vitro with all three α2ARAs. BMD significantly increased soluble APPα (sAPPα) levels at 3 and 8 weeks (2.1 and 1.6-fold) in vivo and in vitro with the CoCl2 and UV-light insults. Furthermore, treatment of UV-insulted cells with an sAPPα antibody significantly reduced cell viability compared with BMD-treated control (52%), co-treatment (33%) and untreated control (27%). Finally, we show that α2ARAs modulate levels of laminin and MMP-9 in RGCs, potentially linked to changes in Aβ through APP processing. Together, these results provide new evidence that α2ARAs are neuroprotective through their effects on the Aβ pathway and sAPPα, which to our knowledge, is the first description. Studies have identified the need for α-secretase activators and sAPPα-mimetics in neurodegeneration; α2ARAs, already clinically available, present a promising therapy, with applications not only to reducing RGC death in glaucoma but also other neurodegenerative processes involving Aβ.

Gamma frequency entrainment attenuates amyloid load and modifies microglia : Nature : Nature Research

Changes in gamma oscillations (20–50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer’s disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40 Hz), but not other frequencies, reduces levels of amyloid-β (Aβ)1–40 and Aβ 1–42 isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with Aβ. Subsequently, we designed a non-invasive 40 Hz light-flickering regime that reduced Aβ1–40 and Aβ1–42 levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer’s-disease-associated pathology."

Amyloidogenic amyloid-β-peptide variants induce microbial agglutination and exert antimicrobial activity : Scientific Reports

Amyloid-β (Aβ) peptides are the main components of the plaques found in the brains of patients with Alzheimer’s disease. However, Aβ peptides are also detectable in secretory compartments and peripheral blood contains a complex mixture of more than 40 different modified and/or N- and C-terminally truncated Aβ peptides. Recently, anti-infective properties of Aβ peptides have been reported. Here, we investigated the interaction of Aβ peptides of different lengths with various bacterial strains and the yeast Candida albicans. The amyloidogenic peptides Aβ1-42, Aβ2-42, and Aβ3p-42 but not the non-amyloidogenic peptides Aβ1-40 and Aβ2-40 bound to microbial surfaces. As observed by immunocytochemistry, scanning electron microscopy and Gram staining, treatment of several bacterial strains and Candida albicans with Aβ peptide variants ending at position 42 (Aβx-42) caused the formation of large agglutinates. These aggregates were not detected after incubation with Aβx-40. Furthermore, Aβx-42 exerted an antimicrobial activity on all tested pathogens, killing up to 80% of microorganisms within 6 h. Aβ1-40 only had a moderate antimicrobial activity against C. albicans. Agglutination of Aβ1-42 was accelerated in the presence of microorganisms. These data demonstrate that the amyloidogenic Aβx-42 variants have antimicrobial activity and may therefore act as antimicrobial peptides in the immune system.

The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease : Nature

Alzheimer’s disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating—Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease : Scientific Reports

Severe amyloidosis and plaque-localized neuro-inflammation are key pathological features of Alzheimer’s disease (AD). In addition to astrocyte and microglial reactivity, emerging evidence suggests a role of gut microbiota in regulating innate immunity and influencing brain function. Here, we examine the role of the host microbiome in regulating amyloidosis in the APPSWE/PS1ΔE9 mouse model of AD. We show that prolonged shifts in gut microbial composition and diversity induced by long-term broad-spectrum combinatorial antibiotic treatment regime decreases Aβ plaque deposition. We also show that levels of soluble Aβ are elevated and that levels of circulating cytokine and chemokine signatures are altered in this setting. Finally, we observe attenuated plaque-localised glial reactivity in these mice and significantly altered microglial morphology. These findings suggest the gut microbiota community diversity can regulate host innate immunity mechanisms that impact Aβ amyloidosis.

Bacterial Amyloid and DNA are Important Constituents of Senile Plaques: Further Evidence of the Spirochetal and Biofilm Nature of Senile Plaques.

It has long been known that spirochetes form clumps or micro colonies in vitro and in vivo. Cortical spirochetal colonies in syphilitic dementia were considered as reproductive centers for spirochetes. Historic and recent data demonstrate that senile plaques in Alzheimer's disease (AD) are made up by spirochetes. Spirochetes, including Borrelia burgdorferi, are able to form biofilm in vitro. Senile plaques are also reported to contain elements of biofilm constituents. We expected that AβPP and Aβ (the main components of senile plaques) also occur in pure spirochetal biofilms, and bacterial DNA (an important component of biofilm) is also present in senile plaques. Histochemical, immunohistochemical, and in situ hybridization techniques and the TUNEL assay were used to answer these questions. The results obtained demonstrate that Aβ and DNA are key components of both pure spirochetal biofilms and senile plaques in AD and confirm the biofilm nature of senile plaques. These observations validate previous observations that AβPP and/or an AβPP-like amyloidogenic protein are an integral part of spirochetes, and indicate that bacterial amyloid is a constituent of senile plaques. DNA fragmentation in senile plaques further confirms their bacterial nature and provides biochemical evidence for spirochetal cell death. Spirochetes evade host defenses, locate intracellularly, form more resistant atypical forms and notably biofilms, which contribute to and sustain chronic infection and inflammation and explain the slowly progressive course of dementia in AD. To consider co-infecting microorganisms is equally important, as multi-species biofilms may result in a higher resistance to treatments and a more severe dementia.

Chronic Toxoplasma gondii infection enhances β-amyloid phagocytosis and clearance by recruited monocytes. - PubMed - NCBI

 "INTRODUCTION:
Alzheimer's disease (AD) is associated with the accumulation of β-amyloid (Aβ) as senile plaques in the brain, thus leading to neurodegeneration and cognitive impairment. Plaque formation depends not merely on the amount of generated Aβ peptides, but more importantly on their effective removal. Chronic infections with neurotropic pathogens, most prominently the parasite Toxoplasma (T.) gondii, are frequent in the elderly, and it has been suggested that the resulting neuroinflammation may influence the course of AD. In the present study, we investigated how chronic T. gondii infection and resulting neuroinflammation affect plaque deposition and removal in a mouse model of AD.

RESULTS:
Chronic infection with T. gondii was associated with reduced Aβ and plaque load in 5xFAD mice. Upon infection, myeloid-derived CCR2(hi) Ly6C(hi) monocytes, CCR2(+) Ly6C(int), and CCR2(+) Ly6C(low) mononuclear cells were recruited to the brain of mice. Compared to microglia, these recruited mononuclear cells showed highly increased phagocytic capacity of Aβ ex vivo. The F4/80(+) Ly6C(low) macrophages expressed high levels of Triggering Receptor Expressed on Myeloid cells 2 (TREM2), CD36, and Scavenger Receptor A1 (SCARA1), indicating phagocytic activity. Importantly, selective ablation of CCR2(+) Ly6C(hi) monocytes resulted in an increased amount of Aβ in infected mice. Elevated insulin-degrading enzyme (IDE), matrix metalloproteinase 9 (MMP9), as well as immunoproteasome subunits β1i/LMP2, β2i/MECL-1, and β5i/LMP7 mRNA levels in the infected brains indicated increased proteolytic Aβ degradation. Particularly, LMP7 was highly expressed by the recruited mononuclear cells in the brain, suggesting a novel mechanism of Aβ clearance.

CONCLUSIONS:
Our results indicate that chronic Toxoplasma infection ameliorates β-amyloidosis in a murine model of AD by activation of the immune system, specifically by recruitment of Ly6C(hi) monocytes and by enhancement of phagocytosis and degradation of soluble Aβ. Our findings provide evidence for a modulatory role of inflammation-induced Aβ phagocytosis and degradation by newly recruited peripheral immune cells in the pathophysiology of AD."



'via Blog this'

Protective Effect of Amyloid-β Peptides Against Herpes Simplex Virus-1 Infection in a Neuronal Cell Culture Model - IOS Press

Senile amyloid plaques are one of the main hallmarks of Alzheimer’s disease (AD). They correspond to insoluble deposits of amyloid-β peptides (Aβ) and are responsible for the inflammatory response and neurodegeneration that lead to loss of memory. Recent data suggest that Aβ possess antimicrobial and anti-viral activity in vitro. Here, we have used cocultures of neuroglioma (H4) and glioblastoma (U118-MG) cells as a minimal in vitro model to investigate whether Aβ is produced by neuroglioma cells and whether this could result in protective anti-viral activity against HSV-1 infection. Results showed that H4 cells secreted Aβ 42 in response to HSV-1 challenge and that U118-MG cells could rapidly internalize Aβ 42. Production of pro-inflammatory cytokines TNFα and IL-1β by H4 and U118-MG cells occurred under basal conditions but infection of the cells with HSV-1 did not significantly upregulate production. Both cell lines produced low levels of IFNα. However, extraneous Aβ 42 induced strong production of these cytokines. A combination of Aβ 42 and HSV-1 induced production of pro-inflammatory cytokines TNFα and IL-1β, and IFNα in the cell lines. The reported anti-viral protection of Aβ 42 was revealed in transfer experiments involving conditioned medium (CM) of HSV-1-infected H4 cells. CM conferred Aβ-dependent protection against HSV-1 replication in de novo cultures of H4 cells challenged with HSV-1. Type 1 interferons did not play a role in these assays. Our data established that H4 neuroglioma cells produced Aβ 42 in response to HSV-1 infection thus inhibiting secondary replication. This mechanism may play a role in the etiology of AD.

The case for rejecting the amyloid cascade hypothesis : Nature Neuroscience : Nature Publishing Group

Alzheimer's disease (AD) is a biologically complex neurodegenerative dementia. Nearly 20 years ago, with the combination of observations from biochemistry, neuropathology and genetics, a compelling hypothesis known as the amyloid cascade hypothesis was formulated. The core of this hypothesis is that it is pathological accumulations of amyloid-β, a peptide fragment of a membrane protein called amyloid precursor protein, that act as the root cause of AD and initiate its pathogenesis. Yet, with the passage of time, growing amounts of data have accumulated that are inconsistent with the basically linear structure of this hypothesis. And while there is fear in the field over the consequences of rejecting it outright, clinging to an inaccurate disease model is the option we should fear most. This Perspective explores the proposition that we are over-reliant on amyloid to define and diagnose AD and that the time has come to face our fears and reject the amyloid cascade hypothesis.

Time to Dismount | Journal of Alzheimer's Disease

The field of Alzheimer research has reached an impasse after more than 100,000 clinical and scientific papers published in the last 40 years, because there is yet no hope, no effective treatment, and no knowledge of what causes this dementia.

It has become increasingly clear that part of the explanation for the lack of therapeutic advancement in Alzheimer’s disease (AD) lies in the unyielding quagmire resulting from the premise that AD is caused by the excessive production in the brain of a sticky substance called amyloid-β (Aβ). However, considerable data indicates this conclusion is not supported by evidence-based medicine, especially from a clinical perspective.

The village wisdom, passed on from generation to generation, used to say that when you discover that you are a riding a dead horse, the best strategy is to dismount. It is time to get off the dead horse that so far has only provided knee-jerk dogma and an absence of clinically useful measures. This action will be helpful so we can get on with more constructive research that searches for a valid pathway to defeat one of the most important medical challenges of this century.

β-Amyloid peptides display protective activity against the human Alzheimer's disease-associated herpes simplex virus-1.

Amyloid plaques, the hallmark of Alzheimer's disease (AD), contain fibrillar β-amyloid (Aβ) 1-40 and 1-42 peptides. Herpes simplex virus 1 (HSV-1) has been implicated as a risk factor for AD and found to co-localize within amyloid plaques. Aβ 1-40 and Aβ 1-42 display anti-bacterial, anti-yeast and anti-viral activities. Here, fibroblast, epithelial and neuronal cell lines were exposed to Aβ 1-40 or Aβ 1-42 and challenged with HSV-1. Quantitative analysis revealed that Aβ 1-40 and Aβ 1-42 inhibited HSV-1 replication when added 2 h prior to or concomitantly with virus challenge, but not when added 2 or 6 h after virus addition. In contrast, Aβ 1-40 and Aβ 1-42 did not prevent replication of the non-enveloped human adenovirus. In comparison, antimicrobial peptide LL-37 prevented HSV-1 infection independently of its sequence of addition. Our findings showed also that Aβ 1-40 and Aβ 1-42 acted directly on HSV-1 in a cell-free system and prevented viral entry into cells. The sequence homology between Aβ and a proximal transmembrane region of HSV-1 glycoprotein B suggested that Aβ interference with HSV-1 replication could involve its insertion into the HSV-1 envelope. Our data suggest that Aβ peptides represent a novel class of antimicrobial peptides that protect against neurotropic enveloped virus infections such as HSV-1. Overproduction of Aβ peptide to protect against latent herpes viruses and eventually against other infections, may contribute to amyloid plaque formation, and partially explain why brain infections play a pathogenic role in the progression of the sporadic form of AD.

Characterizing Apolipoprotein E ε4 Carriers and Noncarriers With the Clinical Diagnosis of Mild to Moderate Alzheimer Dementia and Minimal β-Amyloid Peptide Plaques

Importance  β-Amyloid peptide (Aβ) plaques are a cardinal neuropathologic feature of Alzheimer disease (AD), yet more than one-third of apolipoprotein E ε4 (APOE4) noncarriers with the clinical diagnosis of mild to moderate Alzheimer dementia may not meet positron emission tomographic criteria for significant cerebral amyloidosis.

Objectives  To clarify the percentage of APOE4 carriers and noncarriers with the primary clinical diagnosis of mild to moderate Alzheimer dementia near the end of life and minimal Aβ plaques noted at autopsy and the extent to which these cases are associated with appreciable neurofibrillary degeneration or a primary neuropathologic diagnosis other than AD.

Design, Setting, and Participants  Data on participants included in this study were obtained from the National Alzheimer Coordinating Center’s Uniform Data Set, which comprises longitudinal clinical assessments performed at the AD centers funded by the National Institute on Aging. Neuropathology data are available for the subset of participants who died. A total of 100 APOE4 noncarriers and 100 APOE4 carriers had the primary clinical diagnosis of mild to moderate Alzheimer dementia at their last visit, known APOE4 genotype, died within the ensuing 24 months, and underwent neuropathologic evaluation on autopsy. The study was conducted from September 1, 2005, to September 1, 2012; analysis was performed from October 9, 2012, to March 20, 2015.

Main Outcomes and Measures  Standardized histopathologic assessments of AD neuropathologic changes were the primary measures of interest in this study, specifically Consortium to Establish a Registry for Alzheimer’s Disease neuritic plaque density score, diffuse plaque density score, and Braak stage for neurofibrillary degeneration. The distributions of scores for these measures were the primary outcomes.

Results  Of the 37 APOE4 noncarriers with minimal neuritic plaques, 16 individuals (43.2%) had Braak stages III to VI ratings, and 15 of the others (75.0%) met neuropathologic criteria for other dementia-related diseases. Of the 13 APOE4carriers with minimal neuritic plaques, 6 individuals (46.2%) had Braak stages III to VI ratings and met neuropathologic criteria for other dementia-related diseases. Similarly, of the 7 APOE4 carriers with minimal neuritic plaques and Braak stages 0 to II, 4 participants (57.1%) were thought to have pathologic changes and alterations resulting from non-AD neuropathologic features.

Conclusions and Relevance  In this study, more than one-third of APOE4 noncarriers with the primary clinical diagnosis of mild to moderate Alzheimer dementia had minimal Aβ plaque accumulation in the cerebral cortex and, thus, may show limited or no benefit from otherwise effective anti-Aβ treatment. Almost half of the participants with a primary clinical diagnosis of mild to moderate Alzheimer dementia and minimal Aβ plaque accumulation had an extensive topographic distribution of neurofibrillary degeneration. Additional studies are needed to better understand and provide treatment for patients with this unexpectedly common cliniconeuropathologic condition.

Herpes simplex virus type 1 infection in neurons leads to production and nuclear localization of APP intracellular domain (AICD): implications for Alzheimer's disease pathogenesis.

Several data indicate that neuronal infection with herpes simplex virus
type 1 (HSV-1) causes biochemical alterations reminiscent of Alzheimer's
disease (AD) phenotype. They include accumulation of amyloid-β (Aβ),
which originates from the cleavage of amyloid precursor protein (APP),
and hyperphosphorylation of tau protein, which leads to neurofibrillary
tangle deposition. HSV-1 infection triggers APP processing and drives
the production of several fragments including APP intracellular domain
(AICD) that exerts transactivating properties. Herein, we analyzed the
production and intracellular localization of AICD following HSV-1
infection in neurons. We also checked whether AICD induced the
transcription of two target genes, neprilysin (nep) and glycogen
synthase kinase 3β (gsk3β), whose products play a role in Aβ clearance
and tau phosphorylation, respectively. Our data indicate that HSV-1 led
to the accumulation and nuclear translocation of AICD in neurons.
Moreover, results from chromatin immunoprecipitation assay showed that
AICD binds the promoter region of both nep and gsk3β. Time course
analysis of NEP and GSK3β expression at both mRNA and protein levels
demonstrated that they are differently modulated during infection. NEP
expression and enzymatic activity were initially stimulated but, with
the progression of infection, they were down-regulated. In contrast,
GSK3β expression remained nearly unchanged, but the analysis of its
phosphorylation suggests that it was inactivated only at later stages of
HSV-1 infection. Thus, our data demonstrate that HSV-1 infection
induces early upstream events in the cell that may eventually lead to Aβ
deposition and tau hyperphosphorylation and further suggest HSV-1 as a
possible risk factor for AD.

Does Amyloid Kill in Alzheimer’s, Heal in MS?

Beta-amyloid, ...........a suspected culprit in Alzheimer's disease but many amyloid directed trials have failed:-

Steinman’s team questioned whether aβ is a villain at all. This helped them to try an unusual experiment that may pay off in spades—though it may confuse a lot of people along the way.Noticing some aβ in MS lesions, they created a synthetic version of it and gave it systemically to MS-model mice to figure out its purpose there. To his shock, it reversed their paralysis for as long as it was administered. He reported this in Science Translational Medicine in 2012. In 2013, he reported in that same journal that even small, pared down hexa-peptides from aβ—and from other amyloid-forming proteins like Alpha-b crystalline and tau—could reverse paralysis in MS-model mice. Now “we are tackling neuro-inflammation using amyloid hexa-peptides mostly in models of MS, which is a disease of neuro-inflammation,” he told Bioscience Technology. “In that situation, our amyloid structures definitely make mice better. We have also found the absence of such amyloid structures makes mice worse, whether you knock out aβ or Alpha b-crystallin, or tau, or prion. This could be a whole new potential MS therapy.”

Clioquinol promotes the degradation of metal-dependent amyloid-β (Aβ) oligomers to restore endocytosis and ameliorate Aβ toxicity

Identifying disease-modifying therapies for Alzheimer’s disease (AD) has been an insurmountable challenge. To provide a new discovery tool for high-throughput compound screening, we used a simple yeast model that makes toxic amounts of β-amyloid (Aβ), a peptide central to AD pathology. Previous genetic analysis established that Aβ compromises yeast biology in a manner relevant to human AD. We screened 140,000 compounds for reversal of toxicity and identified a class of protective metal-binding compounds related to clioquinol (CQ), a compound that alleviates Aβ toxicity in mouse AD models. Treating yeast with CQ promoted rapid degradation of Aβ oligomers, rescuing cellular processes perturbed by this insidious peptide and restoring viability. Our approach provides a method for identifying compounds that may eventually help treat AD.

SFN Transgenic Caenorhabditis elegans and transfected cultured cells expressing human Abeta resist infection by salmonella typhimurium

 Our laboratory recently reported that synthetic Abeta peptide has in vitro antimicrobial activity against at least six human pathogens. More recently we presented data suggesting Abeta binding and antimicrobial activity against pathogenic forms of Candida albicans is increased 2-3 orders of magnitude by oligomerization. In this study we present data on the in vivo efficacy of soluble oligomeric Abeta as a protective antimicrobial peptide (AMP). Experiments used cultured transfected cell monolayers and transgenic (Tg) Caenorhabditis elegans as host models and the intracellular bacterial pathogen Salmonella typhimurium as the infecting agent. Data is consistent with a in vivo role for Abeta as an AMP.
METHODS;
Abeta-mediated protection was first tested in a cultured cell monolayer model. Monolayers of naive or transfected cells expressing the 42 residue Abeta isoform (Abeta42) were prepared and infected with S. typhimurium bacteria labeled with red fluorescent protein (Salmonella-RFP) using the gentamycin infection assay protocol. Experiments next characterized resistance to Salmonella-RFP infection in a C. Elegans model. Infection of CL2122 control worms expressing green fluorescent protein (GFP) alone was compared to GMC101 Tg animals co-expressing GFP and Abeta42. Infection in both models was monitored using confocal microscopy, and viability, behavioral and biochemical assays. Experiments included immunochemical and chromatographic characterization of the oligomerization state of Abeta in host models.
RESULTS;
For cultured cells Abeta42 expression was associated with a 1-2 order of magnitude reduction in Salmonella invasion. In addition, survival of transfection Abeta expressing cells was significantly extended compared to naive cells. In the C. elegans infection model the spread of Salmonella-RFP was significantly inhibited in Abeta42 expressing tissues while overall bacterial load was significantly lower for GMC101 Tg worms compared to the CL2122 control strain. Biochemical data was consistent with an Abeta oligomer mediated antimicrobial mechanism.
CONCLUSION; Data is consistent with our previous findings of a potent in vitro antimicrobial activity for Abeta. The new finding confirm that expression of Abeta is also protective against invasive bacterial pathogens in vivo in cultured cells and C. elegans host models. Our data is further evidence that Abeta is an AMP and normally functions as part of the brains innate immune system.