The predominantly pre-synaptic intrinsically disordered protein α-synuclein is prone to misfolding and aggregation in synucleinopathies, such as Parkinson's disease and Dementia with Lewy bodies. For example molecules of the chaperone machinery are often deposited in Lewy bodies.

A new publication describes a vicious cycle in which parts of a chaperone facilitate the accumulation of toxic α-synuclein, which induces proteostatic stress that itself leads to an increase in insoluble fragments of the chaperone.

Molecular chaperones (proteins that assist the conformational folding or unfolding of large proteins) play important roles in protein misfolding diseases. Heat shock proteins are chaperones that protect cells when stressed by elevated temperatures. Heat shock protein 90 (Hsp90) is one of the most common of those chaperone proteins.

In this new publication, authors from Canada, Brazil and Israel show that STI1, the Hsp90 co-chaperone (proteins that assist chaperones ) co-immunoprecipitated α-synuclein, and co-deposited with Hsp90 and Hsp70 in phosphorylated α-synuclein in ubiquitin-positive inclusions in two mouse models of α-synuclein misfolding.

In Parkinson disease human brains, STI1 was increased, and in neurologically healthy brains, STI1 and α-synuclein location correlated. Nuclear Magnetic Resonance analyses revealed direct interaction of α-synuclein with STI1 and indicated that the STI1 domain ( a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest) TPR2A, but not TPR1 or TPR2B domains, interacted with the C-terminal domain of α-synuclein.

Mice over-expressing STI1 and Hsp90ß presented elevated α-synuclein S129 phosphorylation accompanied by inclusions when injected with α-synuclein pre-formed fibrils.

In contrast, reduced STI1 function decreased protein inclusion formation, S129 α-synuclein phosphorylation, while mitigating motor and cognitive deficits as well as mesoscopic brain atrophy in α-synuclein-over-expressing mice.

In conclusion the authors' findings reveal a vicious cycle in which STI1 facilitates the generation and accumulation of toxic α-synuclein conformers, while α-synuclein-induced proteostatic stress increased insoluble STI1 and Hsp90.

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Resting motor threshold is the minimum intensity that evoked a visible contralateral involuntary finger twitch.

Resting motor threshold asymmetry is the absolute difference between the left and right RMT measurements.

Conflicting results have emerged from studies examining the potential of resting motor threshold as a neurophysiological marker for Alzheimer's disease diagnosis and progression.

In this study, the authors estimated the strength of the association between Resting motor threshold measurements and severity of cognitive impairment in a relatively large sample of clinical trial participants with mild to moderate Alzheimer's disease.

Resting motor threshold for each participant was determined by applying single-pulse transcranial magnetic stimulation repeated at varying intensities over left and right sides of the primary motor cortex.

Cognitive impairment was measured with the Montreal Cognitive Assessment and the Alzheimer Disease Assessment Scale - Cognitive scores.

Although the left and right resting motor threshold was lower in CDR 2 than in CDR 1 participants, neither RMT nor RMT asymmetry correlated significantly with cognitive test scores.

In conclusion, authors' study in a large sample size does not support the idea that resting motor threshold is a sensitive marker of cognitive decline/severity in Alzheimer's disease.

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Greater physical activity and cardiorespiratory fitness are associated with reduced age-related cognitive decline and lower risk for dementia. However, significant gaps remain in the understanding of how physical activity and fitness protect the brain from adverse effects of brain aging.

Cardiorespiratory fitness is a physiological attribute defined as the ability for circulatory and respiratory systems to deliver oxygen.

Cardiorespiratory fitness has a positive relationship with functional connectivity of several cortical networks associated with age-related decline. Furthermore it can occur independent of habitual physical activity.

A 2017 article found evidence for a shared mechanism underlying a favourable cardiovascular fitness profile and ALS susceptibility. The scientists did expose three hypothesis but this one had their favors: A genetic predisposition, for example metabolism, could lead to an increased risk of ALS and a beneficial cardiovascular risk profile. But they were unable to find evidence supporting it.

The scientists in this new publication on contrary found no association between common vascular risk factors and cognitive impairment in patients with Amyotrophic Lateral Sclerosis.

In their cohorte 870 patients, 266 had cognitive impairment. yet no cognitive burden from vascular risk factors was found in patients with Amyotrophic Lateral Sclerosis. On the contrary (and as found in many other studies), the authors first observed that type 2 diabetes mellitus and hyperlipidemia showed protective effects against cognitive decline in Amyotrophic Lateral Sclerosis.

Sensitivity analyses of gender did not substantially reverse the risk estimates. : T2DM and hyperlipidemia decrease the risk of cognitive impairment in patients with Amyotrophic Lateral Sclerosis.

So the fitness hypothesis in Amyotrophic Lateral Sclerosis seems less probable or more complex than initially stated.

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Aging is by far the most prominent risk factor for Alzheimer's disease, and both aging and Alzheimer's disease are associated with apparent metabolic alterations. Perturbed cerebral glucose metabolism, an invariant pathophysiological feature of Alzheimer's disease, may be a critical contributor to the pathogenesis of this disease. For this reason, Alzheimer's disease has sometime times being called "Type 3 diabetes mellitus".

Circadian rhythms, type 2 diabetes mellitus and Alzheimer's disease are closely related and interacted with each other.
The authors of a new article on MedRxiv have previously showed circadian disruption aggravated progression of Alzheimer's disease in T2DM mice. Time-restricted feeding is shown to be a potential synchronizer. This study aims to determine whether time-restricted feeding has a protect effect against the circadian disruption-aggravated progression of Alzheimer's disease in type 2 diabetes mellitus.

Six-week-old male diabetic mice and wildtype mice were kept under normal 12:12 light/dark cycles or altered 6:18 light/dark cycles with or without time-restricted feeding period. After eight weeks, three behavioral tests (open field test, novel object recognition test, barnes maze test were performed and the circadian gene expression, body weight, lipid levels and Alzheimer's disease-associated tau phosphorylation were evaluated.
The scientists found altered light/dark cycles contributed to disruptive circadian rhythms in the hippocampus of db/db mice, while time-restricted feeding prevented this effect. time-restricted feeding also ameliorated circadian disruption-aggravated increased body weight and lipid accumulation in db/db mice.

Importantly, the db/db mice under circadian disruption showed impaired cognition accompanied by increased tau phosphorylation, whereas time-restricted feeding reversed these changes. The altered light/dark cycles only affected circadian rhythms but not other indicators like plasma/liver lipids, cognition and tau phosphorylation in the wt/wt mice.

Collectively, time-restricted feeding has a protective effect against altered light/dark cycles-aggravated Alzheimer's disease progression in diabetic mice.

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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).

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. 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 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. 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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