Pathway of Alzheimer's degeneration discovered: Finding is key for future treatment and earlier diagnosis -- ScienceDaily

Scientists at the Montreal Neurological
Institute and Hospital (The Neuro) of McGill University have used a
unique approach to track brain degeneration in Alzheimer's disease,
uncovering a pathway through which degeneration spreads from one region
to another.

Individuals in the early stages of Alzheimer's disease (AD) were
scanned using both structural magnetic resonance imaging (sMRI) and
positron emission tomography (PET). The scientists were interested in
how AD affects the basal forebrain -- a deep brain structure that
supplies the outer cortex with acetylcholine, a neurotransmitter that is
critical for maintaining normal brain function. They found that as
cholinergic neurons in the basal forebrain degenerate, the areas in the
cortex which receive their cholinergic inputs also degenerate.

Lithium May Prevent Neuron Damage In traumatic brain injury Patients - Neuroscience News

According to researchers, lithium, a drug commonly used to treat bipolar disorder, and rapamycin can help to protect neurons from further damage in those with TBI.

Source: Rutgers.

A drug used to treat bipolar disorder and other forms of depression may help to preserve brain function and prevent nerve cells from dying in people with a traumatic brain injury, according to a new Rutgers University study.

In research published in Scientific Reports, Rutgers scientists discovered that lithium – used as a mood stabilizer and to treat depression and bipolar disorder – and rapamycin, a treatment for some forms of cancer, protected nerve cells in the brain and stopped the chemical glutamate from sending signals to other cells and creating further brain cell damage."



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Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice | Brain | Oxford Academic

 Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer’s disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss. Re-establishing translation rates by inhibition of eIF2α-P activity, genetically or pharmacologically, restores memory and prevents neurodegeneration and extends survival. However, the experimental compounds used preclinically are unsuitable for use in humans, due to associated toxicity or poor pharmacokinetic properties. To discover compounds that have anti-eIF2α-P activity suitable for clinical use, we performed phenotypic screens on a NINDS small molecule library of 1040 drugs. We identified two compounds, trazodone hydrochloride and dibenzoylmethane, which reversed eIF2α-P-mediated translational attenuation in vitro and in vivo. Both drugs were markedly neuroprotective in two mouse models of neurodegeneration, using clinically relevant doses over a prolonged period of time, without systemic toxicity. Thus, in prion-diseased mice, both trazodone and dibenzoylmethane treatment restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival. In tauopathy-frontotemporal dementia mice, both drugs were neuroprotective, rescued memory deficits and reduced hippocampal atrophy. Further, trazodone reduced p-tau burden. These compounds therefore represent potential new disease-modifying treatments for dementia. Trazodone in particular, a licensed drug, should now be tested in clinical trials in patients.



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Neurotoxic reactive astrocytes are induced by activated microglia :

"Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1α, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes are abundant in various human neurodegenerative diseases including Alzheimer’s, Huntington’s and Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis. Taken together these findings help to explain why CNS neurons die after axotomy, strongly suggest that A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders, and provide opportunities for the development of new treatments for these diseases."



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Neurotoxic reactive astrocytes are induced by activated microglia : Nature : Nature Research

Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1α, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes are abundant in various human neurodegenerative diseases including Alzheimer’s, Huntington’s and Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis. Taken together these findings help to explain why CNS neurons die after axotomy, strongly suggest that A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders, and provide opportunities for the development of new treatments for these diseases.



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Nature Brain disorders across the lifespan

Brain and other nervous-system disorders impose a disproportionate burden on those in low- and middle-income countries. For over a decade, the Fogarty International Center and its NIH partners have supported research and capacity-building to provide context-sensitive solutions to this public health challenge. This supplement outlines the overarching and intersecting research priorities for addressing causes, prevention, treatment and rehabilitation, as well as opportunities to strengthen scientific capacity that can promote global nervous system health."

Free open access supplement:

A breakdown product of aspirin blocks cell death associated with Alzheimer's, Parkinson's and Huntington's diseases

: "Researchers at the Boyce Thompson Institute and John Hopkins University discovered that salicylic acid, the primary breakdown product of aspirin, binds to GAPDH, thereby stopping it from moving into a cell's nucleus, where it can trigger the cell's death. The study, which appears in the journal PLOS ONE, also suggests that derivatives of salicylic acid may hold promise for treating multiple neurodegenerative diseases."

Reduced cerebral cortical thickness in Non-cirrhotic patients with hepatitis C. - PubMed - NCBI

Hepatitis C virus (HCV) infection is associated with fatigue, depression, and cognitive impairment even in the absence of severe liver fibrosis or cirrhosis. HCV has been hypothesised to cause neurodegenerative changes through low-grade neuroinflammation. Our aim was to examine whether cortical thickness (CTh) differs between chronic HCV patients and healthy controls, suggestive of cortical atrophy. In this case-control study 43 HCV patients without severe liver fibrosis, substance abuse, or comorbid HIV or hepatitis B virus infection, and 43 age and sex matched controls underwent MRI. Cortical thickness was measured using a surface based approach. Participants underwent semi-structured psychiatric interview and fatigue was assessed using the fatigue severity scale. HCV was associated with higher fatigue scores, and 58 % of HCV patients suffered from significant fatigue (p < 0.0001). Depression was observed in 16 % of patients. Areas of significantly reduced CTh were found in both left and right occipital cortex and in the left frontal lobe after correction for multiple comparisons (p < 0.05). No association between fatigue, former substance abuse, or psychotropic medication and CTh was found. No overall difference in cerebral white and grey matter volume was found. The findings support the hypothesis that HCV is associated with neurodegenerative changes.

Neurodegeneration Shown to Result from Impaired Mitochondrial Function | GEN News Highlights | GEN

PET reveals inflammatory cycle in the brain - Medical News Today

Molecular imaging tracks an immune response tied to neurodegenerative disease

Neuroinflammation caused by a reactive immune system could be tripping off the neurodegeneration seen in certain dementias, multiple sclerosis,and other deadly diseases of the nervous system. A novel molecular imaging technique could be the key to understanding how best to treat
these and other devastating diseases, according to a recent study
presented at the 2015 Annual Meeting of the Society of Nuclear Medicine
and Molecular Imaging (SNMMI).
At the heart of this maladaptive immune response are microglia, immune
cells in the central nervous system that can be activated to trigger
neuroinflammation. For this study, researchers used positron emission
tomography (PET) to measure activation of microglia by employing a
molecule from E. coli bacteria called lipopolysaccharide (LPS), or endotoxin. LPS stimulates
the immune system and is accompanied by a radiotracer called carbon-11
PBR28 (C-11 PBR28). This form of molecular imaging allows the minimally
invasive visualization of neuroinflammation. C-11 PBR28, is injected and
binds to translocator proteins expressed on activated microglia. A PET
scanner can then detect the radioactive particles emitted from inside
the brain, representing areas of increased microglial activation before
and after immune stimulation with LPS.
Results of the study showed that peripherally administered LPS led to a substantial
spike in the systemic inflammatory response and levels of reported
sickness, and activated microglia in the central nervous system. 

Systemic Inflammation: A Driver of Neurodegenerative Disease? | ALZFORUM

 Under healthy conditions, microglia look placid. They sit evenly spaced throughout the brain, processes extended, quietly doing their job of scanning for debris. When disease kicks in, these calm cells can transmogrify and end up doing more harm than good. As discussed at “Neuroinflammation in Diseases of the Central Nervous System,” a Keystone meeting held January 25-30 in Taos, New Mexico, the rabble-rousing signals that fire up microglia are not confined to the brain but also come from “below the neck,” said Hugh Perry of the University of Southampton in England. Whether triggered by acute infections or chronic disease, systemic inflammation may amplify microglial responses and exacerbate neurodegeneration, according to researchers at the meeting. They proposed ways to slow disease progression by soothing systemic inflammation.

The human body accumulates inflammatory battle scars as we age, whether through repeated assaults by microbial infections or chronic inflammatory diseases such as diabetes or atherosclerosis. Considering how systemic inflammation might alter the course of neurodegeneration is thus crucial, Perry said. “Old brains are attached to old bodies, and bodies tend to accumulate a lot of pathology over the years,” he said. At the meeting, Perry reported that this pathology primes microglia, making them prone to overreactions that could exacerbate neurodegeneration.

Scientists make connection between genetic variation and immune system in risk for neurodegenerative and other diseases - Medical News Today

Researchers from Brigham and Women's Hospital (BWH), Harvard Medical
School (HMS), the Broad Institute of MIT and Harvard, Massachusetts
General Hospital (MGH), and University of Chicago report findings
demonstrating how genetic variations among healthy, young individuals
can influence immune cell function. Many of those variants are also
genetic risk factors for common diseases such as Alzheimer's disease, diabetes, and multiple sclerosis later in life, offering new insight into disease pathology.
The researchers recruited a subset of 461 volunteers from the
PhenoGenetic Project of African American, East Asian American, or
European American ancestry. Two different types of immune cells - T
cells and monocytes - were purified from each individual's blood,
representing the adaptive and innate arms of immunity, respectively. The
researchers profiled these cells to measure the expression of 19,114
genes in each cell type. They then examined genetic variants throughout
the human genome for their effects on gene expression in these two
representative populations of immune cells.
They discovered that genetic variation influencing a person's risk for multiple sclerosis, rheumatoid arthritis, and type 1diabetes is more likely to control gene activity in T cells
than in monocytes. In contrast, genetic variation that increases one's
risk for neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, shows a striking enrichment of functional effects in monocytes.

Protein clusters implicated in neurodegenerative diseases actually serve to protect brain cells

In two ground-breaking studies, published in the journals PLOS ONE and Nature Communications, Prof. Lederkremer and his team demonstrated that protein clusters are not the cause of toxicity in Huntington's disease.
On the contrary, these aggregates actually serve as a defense mechanism
for "stressed" brain cells. Conducted on tissue cultures using
cutting-edge microscopic technology, their studies identified a
different causative agent—the "stress response" of affected brain cells.

Prof. Lederkremer and his team chose to examine the effect of protein
aggregates in the pathology of Huntington's disease because its genetic
cause is well-known, unlike those of other neurodegenerative diseases,
such as Parkinson's, whose origins remain less clear.


"What we found in this study—a surprise, although we suspected it—was
that damage to the cells, the cell 'stress' that leads to death of
cells, appeared well before the protein aggregates did," said Prof.
Lederkremer. "And even more surprising, when the aggregates finally
appeared, the stress was reduced, in some cases even stopping. The
actual process of forming an aggregate was protective, isolating and
segregating the problematic proteins. This explains why in autopsies of
people who died of Huntington's and other diseases like Alzheimer's or
old age, the protein aggregates in the brains were all quite similar,
reflecting no specific disease link."

PLOS Genetics: Molecular Evidence for the Inverse Comorbidity between Central Nervous System Disorders and Cancers Detected by Transcriptomic Meta-analyses

There is epidemiological evidence that patients with certain Central
Nervous System (CNS) disorders have a lower than expected probability of
developing some types of Cancer. We tested here the hypothesis that
this inverse comorbidity is driven by molecular processes
common to CNS disorders and Cancers, and that are deregulated in
opposite directions. We conducted transcriptomic meta-analyses of three
CNS disorders (Alzheimer's disease, Parkinson's disease and
Schizophrenia) and three Cancer types (Lung, Prostate, Colorectal)
previously described with inverse comorbidities. A significant
overlap was observed between the genes upregulated in CNS disorders and
downregulated in Cancers, as well as between the genes downregulated in
CNS disorders and upregulated in Cancers. We also observed expression
deregulations in opposite directions at the level of pathways. Our
analysis points to specific genes and pathways, the upregulation of
which could increase the incidence of CNS disorders and simultaneously
lower the risk of developing Cancer, while the downregulation of another
set of genes and pathways could contribute to a decrease in the
incidence of CNS disorders while increasing the Cancer risk. These
results reinforce the previously proposed involvement of the PIN1 gene, Wnt and P53 pathways, and reveal potential new candidates, in particular related with protein degradation processes.

Single Amino Acid Repeats Connect Viruses to Neurodegeneration.

We report on a high level of octapeptide matching between HCV, HIV-2,
MPV, MUV, EBV, HHV-6, and CMV, and human brain antigens that, when
altered, have been specifically associated with neuropathologies such as
amyotrophic lateral sclerosis, spinocerebellar ataxia, frontotemporal
degeneration, Huntington disease, Parkinson disease, cognitive
impairment, aphasia and oculomotor apraxia. Quantitatively, the extent
of the viral octapeptide sharing with neurodegeneration-associated
proteins is in excess when analyzed in a stochastic expectation context.
Qualitatively, two main features characterize the peptide matching: 1)
many common sequences are single amino acid repeats, and 2) mostly, the
shared octapeptides are part of experimentally validated epitopes, thus
suggesting an immune crossreactive potential of the viral peptides
shared with brain antigens involved in neurodegeneration. The present
study may have relevance for peptide-based therapeutic approaches to
block potential autoimmune crossreactions in neurological diseases and
dysfunctional behavior.

Natural plant compound prevents Alzheimer's disease in mice -- ScienceDaily

A chemical that's found in fruits and vegetables from strawberries to
cucumbers appears to stop memory loss that accompanies Alzheimer's
disease in mice, scientists at the Salk Institute for Biological Studies
have discovered. In experiments on mice that normally develop
Alzheimer's symptoms less than a year after birth, a daily dose of the
compound -- -a flavonol called fisetin -- -prevented the progressive
memory and learning impairments. The drug, however, did not alter the
formation of amyloid plaques in the brain, accumulations of proteins
which are commonly blamed for Alzheimer's disease. The new finding
suggests a way to treat Alzheimer's symptoms independently of targeting
amyloid plaques.

Vitamin E is essential for Purkinje neuron integrity.

Alpha-tocopherol (vitamin E) is an essential dietary antioxidant with important neuroprotective functions. Alpha-tocopherol deficiency manifests primarily in neurological pathologies, notably cerebellar dysfunctions such as spinocerebellar ataxia. To study the roles of α-tocopherol in the cerebellum, we used the Ttpa^-/- mice which lack the tocopherol transfer protein (TTP) and are a faithful model of vitamin E deficiency and oxidative stress. When fed vitamin E deficient diet, Ttpa^-/- mice had un-detectable levels of α-tocopherol in plasma and several brain regions. Dietary supplementation with α-tocopherol normalized plasma levels of the vitamin, but only modestly increased its levels in the cerebellum and prefrontal cortex, indicating a critical function of brain TTP. Vitamin E deficiency caused an increase in cerebellar oxidative stress evidenced by increased protein nitrosylation, which was prevented by dietary supplementation with the vitamin. Concomitantly, vitamin E deficiency precipitated cellular atrophy and diminished dendritic branching of Purkinje neurons, the predominant output regulator of the cerebellar cortex. The anatomic decline induced by vitamin E deficiency was paralleled by behavioral deficits in motor coordination and cognitive functions that were normalized upon vitamin E supplementation. These observations underscore the essential role of vitamin E and TTP in maintaining CNS function, and support the notion that α-tocopherol supplementation may comprise an effective intervention in oxidative stress-related neurological disorders.

Low vitamin D causes brain damage

"In addition to being essential for maintaining bone health, newer evidence shows that vitamin D serves important roles in other organs and tissue, including the brain. Published in Free Radical Biology and Medicine, the UK study showed that middle-aged rats that were fed a diet low in vitamin D for several months developed free radical damage to the brain, and many different brain proteins were damaged as identified by redox proteomics. These rats also showed a significant decrease in cognitive performance on tests of learning and memory."

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JCI - Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration

Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator–like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.

When cells 'eat' their own mitochondrial power plants: Scientists solve mystery of basic cellular process

 Cardiolipins, named because they were first found in heart tissue, are a component on the inner membrane of mitochondria. When a mitochondrion is damaged, the cardiolipins move from its inner membrane to its outer membrane, where they encourage the cell to destroy the entire mitochondrion.

However, that is only part of the process, says Charleen T. Chu, M.D., Ph.D., professor and the A. Julio Martinez Chair in Neuropathology in the Pitt School of Medicine's Department of Pathology, another senior author of the study. "It's not just the turkey timer going off; it's a question of who's holding the hot mitt to bring it to the dining room?" That turns out to be a protein called LC3. One part of LC3 binds to cardiolipin, and LC3 causes a specialized structure to form around the mitochondrion to carry it to the digestive centers of the cell.