Corticogenesis is the process in which the cerebral cortex of the brain is formed during the development of the nervous system. The cortex is the outer layer of the brain and is composed of up to six layers. Neurons formed in the ventricular zone migrate to their final locations in one of the six layers of the cortex. The process occurs between gestational weeks seven to 18 in humans.

Alpha-synuclein and tau are abundant multifunctional neuronal proteins, and their intracellular deposits have been linked to many neurodegenerative diseases. The Alzheimer's disease is defined by extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau protein.

However, accumulating evidence suggests that the presynaptic protein α-synuclein, which is usually associated with synucleinopathies like Parkinson's disease, is also involved in the pathophysiology of AD.

Despite the disease relevance, Alpha-synuclein and tau physiological roles remain elusive, as mice with knockout of either of these genes do not exhibit overt phenotypes.

Shengming Wang and colleagues from China and Japan, hypothesized functional cooperation of αSyn and tau during corticogenesis. To reveal this cooperation, they generated a mice model where αSyn and tau genes were deleted and characterized the functional crosstalk between these proteins during brain development.

Intriguingly, deletion of αSyn and tau reduced Notch signaling and accelerated interkinetic nuclear migration of G2 phase at early embryonic stage.

This significantly altered the balance between the proliferative and neurogenic divisions of progenitor cells, resulting in an overproduction of early-born neurons and enhanced neurogenesis, by which the brain size was enlarged during the embryonic stage in both sexes.

On the other hand, loss of αSyn and tau also perturbed gliogenesis at later embryonic stage, as well as the subsequent glial expansion and maturation at postnatal brain. The expansion and maturation of macroglial cells were suppressed in the αSyntau postnatal brain, which in turn reduced the male αSyntau brain size and cortical thickness to less than the control values.

The authors' findings provide new mechanistic insights and extend therapeutic opportunities for neurodegenerative diseases caused by aberrant αSyn and tau.

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Plasma exchange (PE) with albumin replacement is currently being investigated by several organisations as a new therapeutic approach for Alzheimer's disease (AD). enter image description here

Routine PE removal of an AD patient's plasma would favor elimination of albumin‐bound β amyloid , and possibly, other pathogenic elements. In addition, replacement with fresh therapeutic albumin can restore the antioxidant capacity of AD patient plasma, as albumin is highly oxidized and glycated. Furthermore, a therapeutic action at the vascular level can have a positive impact on dementia.

This new study by Gemma Cuberas-Borrós and colleagues from Spain, was designed to detect structural and functional brain changes in Alzheimer's disease patients treated with therapeutic plasma exchange with albumin replacement, as part of the recent AMBAR phase 2b/3 clinical trial. The AMBAR trial enrolled patients at 41 sites: 19 in Spain and 22 in the USA.

Mild-to-moderate Alzheimer's disease patients were randomized into four arms: three arms receiving plasma exchange with albumin, and a placebo arm.

There were two phases for treatment administration:

  • During intensive treatment phase, the three treatment groups received weekly conventional therapeutic PE (TPE) with albumin (Albutein® 5%, Grifols) replacement, through peripheral or central venous access, for 6 weeks.
  • This was followed by a 12-month maintenance period with monthly low-volume PE (LVPE) during which three different treatment modalities were administered.

During the 12-month maintenance period: - one group received LVPE with low-dose (20 g; 100 mL) 20% albumin (Albutein® 20%, Grifols); - one group received low-dose albumin alternated with low-dose (10 g; 200 mL) IVIG (Flebogamma® 5% DIF, Grifols) every 4 months; - one group received high-dose (40 g; 200 mL) 20% albumin alternated with high-dose (20 g; 400 mL) IVIG every 4 months.

The high albumin + IVIG group showed no statistically significant reduction of right hippocampus. MRI analyses of selected subcortical structures showed fewer volume changes from baseline to final visit in the high albumin + IVIG treatment group. I.e., the smallest percent decline in metabolism, and least progression of defect compared to placebo.

Particularly in moderate AD patients, there was a significant difference in the extension of defect pattern between high albumin + IVIG and the rest of treatment arms.

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Although Amyotrophic Lateral Sclerosis is considered a motor neuron disorder, neuroinflammation also plays an important role. How a cell dies is critical, as it can drive local immune activation and tissue damage. Classical apoptosis engages several mechanisms to evoke "immunologically silent" responses, whereas other forms of programmed death such as pyroptosis, necroptosis, and ferroptosis release molecules that can potentiate immune responses and inflammation. enter image description here In this new study, the authors Evelien Van Schoor, Dietmar Rudolf Thal and colleagues (including Albert C Ludolph) of Ulm and Leuven universities, determined the expression and distribution of the inflammasome and pyroptosis effector proteins in post-mortem brain and spinal cord from Amyotrophic Lateral Sclerosis patients and controls, as well as in symptomatic and asymptomatic TDP-43 transgenic and wild-type mice.

The authors evaluated its correlation with the presence of TDP-43 pathological proteins and neuronal loss. Expression of pyroptosis effector protein cleaved Gasdermin D (GSDMD), and IL-18 was detected in microglia in human Amyotrophic Lateral Sclerosis motor cortex and spinal cord, indicative of canonical inflammasome-triggered pyroptosis activation.

The number of cleaved GSDMD-positive precentral white matter microglia was increased compared to controls and correlated with a decreased neuronal density in human Amyotrophic Lateral Sclerosis motor cortex. Neither of this was observed in the spinal cord.

Similar results were obtained in TDP-43 mice model, where microglial pyroptosis activation was significantly increased in the motor cortex upon symptom onset, and correlated with neuronal loss. yet there was no significant correlation with the presence of TDP-43 pathological proteins both in human and mouse tissue.

The authors' findings emphasize the importance of microglial NLRP3 inflammasome-mediated pyroptosis activation for neuronal degeneration in Amyotrophic Lateral Sclerosis and pave the way for new therapeutic strategies counteracting motor neuron degeneration in Amyotrophic Lateral Sclerosis by inhibiting microglial inflammasome/pyroptosis activation.

As a commentary on this article, we can observe there are some rationales for testing the efficacy of fumarates in ALS models. Dimethyl fumarate (DMF) is an ester of fumaric acid, which can be isolated from the plant Fumaria officinalis. In folk medicine, the herb has been used for skin diseases, rheumatism, arteriosclerosis, constipation and cystitis. In Germany it was licensed under the brand name Fumaderm and is still used today.

DMF ameliorated LPS and ATP-induced NLRP3 inflammasome activation by reducing IL-1β, IL-18, caspase-1, and NLRP3 levels, reactive oxygen species formation and damage, and inhibiting pyroptotic cell death in N9 murine microglia via Nrf2/NF-κB pathways. DMF also improved LPS-induced sickness behavior in male mice and decreased caspase-1/NLRP3 levels via Nrf2 activation. Contact the author of this post

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Neuroinflammation, is characterized by excessively activated glial cells and overexpressed inflammatory factors in Alzheimer’s disease (AD).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are most widely used drugs in inhibiting NF-κB signaling pathway, and high-dose of ibuprofen have been confirmed to improve dementia-like symptoms in AD animal models.

Therefore, anti-neuroinflammatory treatment might undermine the positive feedback loop of neuroinflammation and neuronal dysfunction.

But ibuprofen can't make neuronal damages reversed to cure AD completely. So it is necessary to use additional neuroprotective drugs . Calcineurin inhibitor (tacrolimus, FK506), is one of the most effective neuroprotective drug in central nervous system diseases. Moreover, the amelioration of AD-like behavior has been observed in patients taking FK506 enter image description here Xueqin He, Huile Gao from Sichuan and Macau universities, established an ibuprofen and FK506 encapsulated drug co-delivery system, which can target the receptor of advanced glycation endproducts and response to the high level of reactive oxygen species in Alzheimer's disease.

Methods used to get through the blood–brain barrier (BBB) may entail the use of endogenous transport systems, including carrier-mediated transporters (CMT), such as glucose and amino acid carriers, receptor-mediated transcytosis for insulin or transferrin, and the blocking of active efflux transporters such as p-glycoprotein.

Yet traditional CMT-based brain targeting delivery leads to unselective distribution in whole brain because of the homogenous expression of targeted receptors on BBB31. It is therefore important to find targets that are restrictively expressed on BBB of lesion. In AD lesion sites, the receptor of advanced glycation endproducts (RAGE) is specifically and highly expressed on the diseased neurovascular unit, including cerebral vascular endothelial cells, astrocytes and neurons.

As RAGE is highly and specifically expressed on the lesion neurovascular unit of Alzheimer's disease, this property helps to improve specificity of drug targeting the system and reduce unselective distribution in normal brain.

RAP peptide (sequence: CELKVLMEKEL) is a specific ligand of RAGE, which could assist with the transportation of nanoparticles into diseased brain parenchyma through CMT.

Thus, ibuprofen and FK506 delivery can be specifically released in astrocytes of Alzheimer's disease lesion in response to high levels of ROS.

As a result, the cognition of Alzheimer's disease mice was significantly improved and the quantity of A plaques was decreased. Neurotoxicity was also alleviated with structural regeneration and functional recovery of neurons. Besides, the neuroinflammation dominated by NF-B pathway was significantly inhibited with decreased NF-B and IL-1 in the brain. enter image description here Overall, Ibu&FK@RNPs can efficiently and successively target diseased BBB and astrocytes in Alzheimer's disease lesion. Thus it significantly treats Alzheimer's disease by anti-neuroinflammation and neuroprotection.

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It's known since 2017 that some people with Type 2 diabetes have a higher risk of Alzheimer's disease.

A variant of the so-called Alzheimer’s gene, APOE4, seems to interfere with brain cells' ability to use insulin, which may eventually cause the cells to starve and die. Unofficially, it's called Type 3 diabetes. What it refers to is that their brain's insulin utilization or signaling is not functioning. Their risk of developing Alzheimer’s disease is about 10 to 15 times higher.

This new article by Gemma Salvadó and colleagues adds more information on this topic. Glial activation is one of the earliest mechanisms to be altered in Alzheimer's disease. Glial fibrillary acidic protein relates to reactive astrogliosis and can be measured in both cerebrospinal fluid and blood.

Plasma GFAP has been suggested to become altered earlier in Alzheimer's disease than its cerebrospinal fluid counterpart.

Although astrocytes consume approximately half of the glucose-derived energy in the brain, the relationship between reactive astrogliosis and cerebral glucose metabolism is poorly understood. Fluorodeoxyglucose (FDG) is a glucose analog labeled with a positron emitter isotope (18F) that allows measurement of regional cerebral glucose consumption using positron emission tomography (PET).

The Spanish authors aimed to investigate the association between fluorodeoxyglucose (FDG) uptake and reactive astrogliosis, by means of GFAP quantified in both plasma and cerebrospinal fluid for the same participants. GFAP is an astrocytic intermediate filament protein, mainly expressed in the brain.

The ALFA cohort characterized preclinical AD in 2743 cognitively unimpaired individuals, aged between 45 and 75 years old, and enriched for family history of sporadic AD. From this parent cohort, 419 ALFA + participants were selected to be preferentially APOE-ε4 carriers and/or to be adult children of AD patients. These participants underwent a more comprehensive evaluation including a lumbar puncture and an Aβ and [18F]FDG PET.

For this study, the authors included 314 cognitively unimpaired participants from the ALFA + cohort, 112 of whom were amyloid-β positive. Associations between GFAP markers and [18F]FDG uptake were studied.
The authors also investigated whether these associations were modified by Aβ and tau status.

Plasma GFAP was positively associated with glucose consumption in the whole brain, while cerebrospinal fluid GFAP associations with [18F]FDG uptake were only observed in specific smaller areas like temporal pole and superior temporal lobe. These associations persisted when accounting for biomarkers of Aβ pathology but became negative in Aβ-positive and tau-positive participants in similar areas of Alzheimer's disease-related hypometabolism.

Higher astrocytic reactivity, probably in response to early Alzheimer's disease pathological changes, is related to higher glucose consumption. With the onset of tau pathology, the observed uncoupling between astrocytic biomarkers and glucose consumption might be indicative of a failure to sustain the higher energetic demands required by reactive astrocytes.

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Over the years, the scientific community has sought improvements in the life quality of patients diagnosed with Alzheimer's disease. Synaptic loss and neuronal death observed in the regions responsible for cognitive functions represent an irreversible progressive disease that is clinically characterized by impaired cognitive and functional abilities, along with behavioral symptoms. Currently, image and body fluid biomarkers can provide early dementia diagnostic, being it the best way to slow the disease's progression. The first signs of Alzheimer's disease development are still complex, the existence of individual genetic and phenotypic characteristics about the disease makes it difficult to standardize studies on the subject. The answer seems to be related between Aβ and tau proteins. Aβ deposition in the medial parietal cortex appears to be the initial stage of Alzheimer's disease, but it does not have a strong correlation with neurodegeneration. The strongest link between symptoms occurs with tau aggregation, which antecede Aβ deposits in the medial temporal lobe, however, the protein can be found in cognitively healthy older people. The answer to the question may lie in some catalytic effect between both proteins. Amid so many doubts, Aducanumab was approved, which raised controversies and results intense debate in the scientific field. Abnormal singling of some blood biomarkers produced by adipocytes under high lipogenesis, such as TNFα, leptin, and interleukin-6, demonstrate to be linked to neuroinflammation worsens, diabetes, and also severe cases of COVID-19, howsoever, under higher lipolysis, seem to have therapeutic anti-inflammatory effects in the brain, which has increasingly contributed to the understanding of Alzheimer's disease. In addition, the relationship of severe clinical complications caused by Sars-CoV-2 viral infection and Alzheimer's disease, go beyond the term "risk group" and may be related to the development of dementia long-term.

Thus, this review summarized the current emerging pharmacotherapies, alternative treatments, and nanotechnology applied in clinical trials, discussing relevant points that may contribute to a more accurate look.

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Blood exchange and Alzheimer's disease

- Posted by admin in English

It's known since some time that there is a link between blood and Alzheimer disease.

For example in 2019, after being dosed with GRF6021, a drug proposed by Alkahest, a California-based startup, Alzheimer's patients in a clinical trial retained memory and mental function for six months - when they would normally be expected to deteriorate. GRF6021, a drug proposed by Alkahest, a California-based startup, is made from the blood of young people.

On contrary a large study found that people who experienced a blood transfusion may be at risk of Alzheimer's disease or may be, because they were transfused with "old blood".

A research team led by Claudio Soto, in the Department of Neurology with McGovern Medical School at UTHealth Houston, with Akihiko Urayama, as first author, performed a series of whole blood exchange treatments to partially replace blood from mice exhibiting Alzheimer's disease-causing amyloid precursor proteins with complete blood from healthy mice of the same genetic background.

The results of the study was published in Molecular Psychiatry.

The development of cerebral amyloid plaques in a transgenic mice model of AD (Tg2576) was significantly reduced by 40–80% through exchanging whole blood with normal blood from wild type mice having the same genetic background. Importantly, such reduction resulted in improvement in spatial memory performance in aged Tg2576 mice.

The exact mechanism by which blood exchange reduces amyloid pathology and improves memory is presently unknown, but measurements of Aβ in plasma soon after blood exchange suggest that mobilization of Aβ from the brain to blood may be implicated.

Their results suggest that a target for AD therapy may exist in the peripheral circulation, which could open a novel disease-modifying intervention for AD. Technologies commonly used in medical practice, such as plasmapheresis or blood dialysis, could 'clean' blood from Alzheimer's patients, reducing the buildup of toxic substances in the brain.

This was suggested recently.

Intravacc, a contract development and manufacturing organization (CDMO) of preventive and therapeutic vaccines and the German Center for Neurogenerative Diseases (DZNE), have been awarded a funding of € 2.5 million from the European Union (EIC Transition Grant) to further develop a prototype C9orf72 ALS vaccine.

Mutations in C9orf72 gene causes excessive repeats of six nucleotides GGGGCC. These extra repeats lead to the production of abnormal proteins, called dipeptide repeat proteins (DPR). Moreover, excessive GGGGCC repeats in the C9orf72 gene also are one of the most common causes of frontotemporal dementia (FTD).

Researchers from the German Center for Neurogenerative Diseases hypothesized that using a vaccine to induce the production of such antibodies by the body’s immune system could be a potential therapy for ALS and FTD linked to C9orf72 gene mutations.

This is a concept close to ASO, but it would make the body continuously targeting those repeats, while ASO work only for a short time after administration.

In recent years, there has been increasing interest in the use of monoclonal antibodies to treat neurodegenerative disorders, with the goal of targeting misfolded intra- or extra-cellular proteins, such as amyloid beta peptide, tau, or alpha-synuclein.

Very recently, the U.S. FDA has approved Aducanumab, a recombinant monoclonal antibody against amyloid beta plaques, for the treatment of Alzheimer's disease patients.

Antibodies show a considerable number of advantages when used for therapeutic purposes. They possess a long half-life, and, due to their nature, they can efficiently target proteins in their physiological state, after post-translational modifications or in a misfolded conformation, with high specificity and affinity.

Yet there were many pre-clinical studies involving antibodies against SOD1 or TDP-43 without much success. In 2019 a study had more success with C9orf72.

Antibodies are big molecules and might pose difficulties in penetrating the CNS due to the natural defense structure of the blood-brain barrier (BBB). The use of single chain antibodies could overcome this issue since they are smaller in size and possess higher cellular penetration capacity.

Antibodies treatment starting at the pre-symptomatic stage often proves less effective when delivered at the symptomatic stage, corroborating the need to evaluate therapeutic efficacy when the pathology has already manifested itself. As sporadic ALS patients are diagnosed only years after the beginning of their symptoms, it is unclear how such therapies could be effective.

What strikes me, is that despite the high number of studies on ALS, all the attempts to make therapies seem to explore only rather improbable paths.

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Plasma-based biomarkers (blood tests) present a promising approach in the research and clinical practice of Alzheimer's disease as they are inexpensive, accessible and minimally invasive. enter image description here Recent studies have demonstrated the prognostic utility of plasma biomarkers of Alzheimer pathology or neurodegeneration, such as pTau-181 and NF-L, yet they do not enable to predict cognitive decline.

In this new publication, scientists conducted an observational cohort study to determine the prognostic utility of plasma biomarkers in predicting progression to dementia for individuals presenting with mild cognitive impairment due to probable Alzheimer's disease.

The scientists used an improved Elisa assay to measure the level of 460 circulating proteins in banked plasma samples of all participants. The authors used a discovery data set comprised 60 individuals with mild cognitive impairment and a validation data set consisting of 21 stable and 21 progressors.

They developed a machine learning model to distinguish progressors from stable and used 44 proteins with significantly different plasma levels in progressors versus stable along with age, sex, education and baseline cognition as candidate features.

A model with age, education, APOE genotype, baseline cognition, plasma pTau-181 and 12 plasma Olink protein biomarker levels was able to distinguish progressors from stable with 86.7% accuracy.

In the validation data set, the model accuracy was 78.6%. The Olink proteins selected by the model included those associated with vascular injury and neuroinflammation.

In addition, to compare these prognostic biomarkers to those that are altered in Alzheimer's disease or other types of dementia relative to controls, the authors analyzed samples from 20 individuals with Alzheimer, 30 with non-Alzheimer dementias and 34 with normal cognition.

The proteins NF-L and PTP-1B were significantly higher in both Alzheimer and non-Alzheimer dementias compared with cognitively normal individuals.

Interestingly, the prognostic markers of decline at the mild cognitive impairment stage did not overlap with those that differed between dementia and control cases.

In summary, authors' findings suggest that plasma biomarkers of inflammation and vascular injury are associated with cognitive decline. Developing a plasma biomarker profile could aid in prognostic deliberations and identify individuals at higher risk of dementia in clinical practice.

Voles are small rodents that are relatives of lemmings and hamsters, but with a stouter body; a longer, hairy tail; a slightly rounder head; smaller eyes and ears. enter image description here The prairie vole is a notable animal model for its monogamous social fidelity, since the male is usually socially faithful to the female, and shares in the raising of pups.

Voles comfort mistreated vole. This type of empathetic behavior has previously been thought to occur only in animals with advanced cognition such as humans, apes and elephants.

This uniqueness in behavior is related to the oxytocin and vasopressin hormones. The oxytocin receptors of the female prairie vole brain are located more densely in the reward system, and have more receptors than other species, which causes 'addiction' to the social behavior.

Considerable work is needed to determine the extent to which research results from vole models may apply to bonding animals such as humans and non-bonding animals such as chimpanzees.

Dextroamphetamine is a central nervous system (CNS) stimulant that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac.

The effects of amphetamine's in humans is mostly derived through increased cellular communication or neurotransmission of dopamine, serotonin, norepinephrine, epinephrine, histamine, CART peptides, endogenous opioids, adrenocorticotropic hormone, corticosteroids, and glutamate.

Previous studies have shown that 3-day d-amphetamine treatment effectively induced conditioned place preferences and impaired pair bonding behaviors in prairie voles. Using this established animal model and treatment regimen, the authors examined the effects of the demonstrated threshold rewarding dose of d-amphetamine on various behaviors and their potential underlying neurochemical systems in the brain of female prairie voles.

A new publication shows that 3-day d-amphetamine injections impaired social recognition and decreased depressive-like behavior in females without affecting their locomotion and anxiety-like behaviors.

D-amphetamine treatment also decreased neuronal activation indicated by the labeling of the early growth response protein 1 as well as the number of neurons double-labeled for Egr-1 and corticotrophin-releasing hormone in the dentate gyrus of the hippocampus and paraventricular nucleus of the hypothalamus in the brain.

Corticotropin is a peptide hormone involved in stress responses. EGR-1 is an important transcription factor in memory formation. It has an essential role in brain neuron epigenetic reprogramming. EGR-1 recruits the TET1 protein that initiates a pathway of DNA demethylation. Removing DNA methylation marks allows the activation of downstream genes. EGR-1, together with TET1, is employed in programming the distribution of methylation sites on brain DNA during brain development, in learning and in long-term neuronal plasticity.

Further, d-amphetamine treatment decreased the number of neurons double-labeled for Egr-1 and tyrosine hydroxylase but did not affect oxytocinergic neurons in the paraventricular nucleus or cell proliferation and neurogenesis markers in the dentate gyrus.

These data not only demonstrate potential roles of the brain corticotrophin-releasing hormone and dopamine systems in mediating disrupted social recognition and depressive-like behaviors by d-amphetamine in female prairie voles, but also further confirm the utility of the prairie vole model for studying interactions between psychostimulants and social behaviors.

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