Protein Clumping Best Blocked Using Specific Compounds at Distinct Disease Stages, Model Suggests

protein clumps and disease

A mathematical model created to more effectively prevent protein clumping, widely thought to underlie diseases like Parkinson’s, found that different potential treatments work best at different disease stages.

As such, this model may help in designing and timing the use of therapies against protein aggregates, and in testing them in clinical trials for Parkinson’s, Alzheimer’s, and other diseases.

The study, “Optimal control strategies for inhibition of protein aggregation,” was published in the journal Proceedings of the National Academy of Sciences.

Protein aggregation is a complex process involving multiple microscopic steps. It starts with an event called primary nucleation, in which misfolded (altered shape) proteins clump together to form fibrils, which then elongate. This first step proceeds slowly, potentially taking up to several decades.

A later event is called secondary nucleation. Here, aggregation speeds up and exponential growth occurs, with existing clumps promoting the formation of new ones. This faster phase is associated with evident disease, and a potential for rapid progression.

Aggregates of misfolded proteins are fairly established treatment targets of Parkinson’s, Alzheimer’s, and other diseases. However, finding a therapy combination and dose regimen that is both effective and of limited toxicity — so that side effects don’t make it unusable — has been challenging.

Recent studies suggest that compounds known as molecular inhibitors (blockers) and targeting different types of aggregates, might be an effective approach. Examples include the anti-cancer treatment bexarotene (marketed as Targretin by Ortho Dermatologists for cutaneous T-cell lymphoma) and antibodies.

To help find the right balance between suppressing aggregation and avoiding toxicity, researchers at the Harvard John A. Paulson School of Engineering and Applied Sciences developed a predictive treatment model that combined the physics of protein aggregation with so-called control theory, which assesses the behavior of dynamic systems in mathematics and engineering.

To test their model, the scientists analyzed data from a disease model, the worm Caenorhabditis elegans, that can be engineered to form amyloid-beta clumps that eventually paralyze the worms. Specifically, they looked at the efficacy of bexarotene and a compound known as DesAb29-36. Both these compounds inhibit the aggregation of amyloid-beta — the main component of senile plaques in Alzheimer’s and of normal aging — but at different steps: bexarotene targets primary nucleation, while DesAb29-36 works to block secondary nucleation.

Investigators found that the optimal approach depends on whether a potential treating is targeting primary or secondary nucleation, and on whether the compound can be effective at non-toxic levels. Compound concentration plays a key role, as low amounts require longer periods of administration. However, if exceeding a critical threshold, it turns toxic so that side effects outweigh benefits.

When they analyzed earlier studies in this worm model of amyloid-beta aggregation, scientists found benefits with increasing but low doses of bexarotene in terms of worm movement at disease onset (larval stages). As levels of bexarotene rose, they found it had the opposite effect on worm mobility, indicating the existence of an optimal dose.

Consistent with the effect of bexarotene on primary nucleation, the model predicted that this therapy would be most effective early in the disease course. It had a demonstrated lack of benefits in adult worms.

In turn, the model predicted that DesAb29-36 would be most effective if administered at a later stage of aggregation, in line with its targeting secondary nucleation.

“Our results pose and answer the question of the link between the molecular basis of protein aggregation and optimal strategies for inhibiting it, opening up avenues for the design of rational therapies to control pathological protein aggregation,” the researchers wrote.

In a university news release written by Leah Burrows, Thomas C. T. Michaels, PhD, a lead study author, said the team’s approach is “unique” and “will allow people to test the efficacy of different compounds against aggregation under optimal conditions.”

“From these optimal conditions,” Michaels added, “one could then extrapolate optimal conditions for a [clinical] trial. So, in this sense, our work could help seed potential trials.”

Added L Mahadevan, PhD, the study’s senior author and a professor of applied mathematics at Harvard University: “Our research highlights the importance of understanding the relationship between the chemical kinetics of protein misfolding, the mechanisms by which drugs inhibit protein aggregation, and the timing of their administration.”

All this, he said, “could have important implications for intervention protocols to prevent pathological protein aggregation.”

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Certain Compounds in Coffee, But Not Caffeine, Seen to Prevent Protein Buildup Linked to Parkinson’s in Early Study

coffee consumption

Chemical compounds in coffee — especially phenylindanes that form during the roasting of coffee beans — appear to prevent the damaging aggregation of amyloid-beta and tau known to play key roles in Parkinson’s and Alzheimer’s disease, researchers report.

Caffeine, in contrast, had no effect on protein buildup in this early lab study, and researchers saw coffee consumption to offer no protection against alpha-synuclein aggregation.

The study, “Phenylindanes in Brewed Coffee Inhibit Amyloid-Beta and Tau Aggregation,” was published in Frontiers in Neuroscience.

Coffee consumption has been suggested to reduce the risk of developing diabetes, various cancers, and neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease. Despite the available evidence, however, it’s unclear what how exactly coffee can help to prevent age-related cognitive decline.

Past studies have reported that caffeine, the main bioactive compound of coffee, can reduce the risk of Parkinson’s both in men and in women who were not taking hormone replacement therapy. It has also been seen to reduce nerve cell death in the substantia nigra – the brain area most affected in Parkinson’s – in mouse models of the disease.

However, recent data also suggests that long-term consumption of caffeine may exacerbate anxiety-related behavioral and psychological symptoms in patients with dementia, counteracting its potential beneficial effects.

These contrasting findings highlight the need to identify those coffee components that may be neuroprotective.

Researchers led by Donald Weaver, MD, PhD, co-director of the Krembil Brain Institute, evaluated the potential of chemical components of coffee to inhibit the buildup of proteins that can drive neurodegenerative diseases like Alzheimer’s and Parkinson’s, in particular: amyloid-beta, tau, and alpha-synuclein.

The team started by examining three types of instant coffees — light roast, dark roast, and decaffeinated dark roast — in terms of their ability to prevent protein aggregates. They tested the instant coffees by adding them to one of these three proteins in an in vitro (laboratory dish) context.

“The effect of caffeine content would be assessed by comparing the activity of caffeinated and decaffeinated dark roast coffee extracts. Further, since it is known that different levels of roasting affect the composition of the coffee brew, comparison of light versus dark roast coffee extracts was also performed,” the researchers wrote.

Dark roast coffee showed the greatest inhibitory effect against tau protein buildup. Interestingly, the level of caffeine in each type of coffee had no impact on tau, amyloid-beta, and alpha-synuclein’s ability to aggregate.

“We were surprised to find that caffeine content did not influence aggregation inhibition, and thus performed a post-hoc analysis of pure caffeine,” the researchers said in the study. “No effect on fibril growth was observed relative to the vehicle control, consistent with the results for caffeinated versus decaffeinated coffee extracts.”

Further experiments found that all coffee extracts could prevent amyloid-beta and tau protein aggregation at 200 μg/mL concentration. Dark roast coffee (with or without caffeine) was seen as more potent in preventing the oligomerization — a chemical form that proteins can take — of amyloid-beta than the light roast extract.

All types of coffee as an instant mix, however, showed an ability to promote alpha-synuclein aggregation at amounts above 100 mg/mL.

To better understand these findings, the team then explored the activity of the six main chemical components of coffee — caffeine, chlorogenic acid, quinic acid, caffeic acid, quercetin, and phenylindane.

Researchers found that most of these compounds — with exception of caffeine and quinic acid for amyloid-beta, and caffeine and caffeic acid for tau — prevented protein aggregation.

Phenylindane was found to hold the strongest inhibitory activity, working as a dual-inhibitor to prevent the formation of amyloid-beta aggregates by 99% and those of tau tangles by 95.2%. Importantly, in later experiments, phenylindanes did not show “pro-aggregation behavior” toward alpha-synuclein, the study reported.

Phenylindanes are formed during the roasting of coffee beans and are found in higher concentrations in dark roast coffees, which have longer roasting times.

“It’s the first time anybody’s investigated how phenylindanes interact with the proteins that are responsible for Alzheimer’s and Parkinson’s,” Ross Mancini, a research fellow in medicinal chemistry at the Krembil institute and the study’s first author, said in a news release.  “The next step would be to investigate how beneficial these compounds are, and whether they have the ability to enter the bloodstream, or cross the blood-brain barrier.”

The team is now investigating if phenylindanes can reduce amyloid-beta, tau and alpha-synuclein loads in cell and animal models of Alzheimer’s and Parkinson’s disease.

Researchers caution that their findings are not recommendation for excessive coffee consumption.

“What this study does is take the epidemiological evidence and try to refine it and to demonstrate that there are indeed components within coffee that are beneficial to warding off cognitive decline,” Weaver said. “It’s interesting, but are we suggesting that coffee is a cure? Absolutely not.”

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Alpha-Synuclein Could Be Biomarker for Non-Motor Symptoms in Parkinson’s, Study Suggests

Alpha-synuclein biomarker

Reduced alpha-synuclein levels in the cerebrospinal fluid (CSF) — the liquid surrounding the brain and spinal cord — are associated with more severe non-motor symptoms in Parkinson’s patients, according to a study.

The study, “CSF α-synuclein inversely correlates with non-motor symptoms in a cohort of PD patients,” published in the journal Parkinsonism and Related Disorders, suggests that measurements of alpha-synuclein could be used as a biomarker for non-motor symptoms in Parkinson’s disease.

Unlike its characteristic motor symptoms, Parkinson’s non-motor symptoms — which include emotional and mood changes, cognitive changes or dementia, fatigue, or hallucinations — still lack reliable predictors.

While motor manifestations are due to degeneration of dopamine-producing neurons in a brain area called the substantia nigra, non-motor complications may be caused by more diverse and non-dopaminergic neurodegenerative processes.

Assessing CSF proteins enables the study of disease-related changes in the brain that occur in neurodegenerative diseases. Such an analysis, along with the identification of biomarkers, are key to developing effective treatments.

Italian researchers in this study hypothesized that widespread degeneration underlying non-motor symptoms may mirror the CSF protein profile, which could be used as a biomarker for these symptoms.

They evaluated the association between non-motor symptom severity and CSF levels of alpha-synuclein — the main component of clumps known as Lewy bodies in the brain of Parkinson’s patients; total tau and one of its altered (phosphorylated) versions that form tangles inside neurons in Parkinson’s disease; and a form of amyloid-beta called 42-amyloid-beta, which is also relevant in Alzheimer’s disease.

A total of 83 individuals were included, 46 with Parkinson’s (24 men, mean age 57.4 years) and 37 controls (22 men, mean age 60.9 years). The control group included participants with non-neurodegenerative conditions receiving a spinal tap for diagnostic purposes, but without signs of motor and cognitive impairment.

Standard clinical scores were used to assess Parkinson’s patients: Non-motor symptoms were measured using the Non Motor Symptoms Scale (NMSS) total and single-item scores, motor symptoms with the Unified Parkinson Disease Rating Scale part 2 and 3 (UPDRS 2-3), and cognition with the Mini Mental State Examination. Evaluations were conducted while patients were on standard antiparkinsonian medications.

The results showed that Parkinson’s patients had lower alpha-synuclein and total tau levels than controls. According to the authors, the reduced amount of alpha-synuclein in the CSF could be attributed to its accumulation in Lewy bodies.

Additionally, the phosphorylated/total tau ratio was significantly higher in Parkinson’s patients than in controls. However, the total tau/alpha-synuclein + 42-amyloid-beta ratio was lower in people with Parkinson’s. Alpha-synuclein at a cut-off value of 1,143 pg/ml showed the highest sensitivity (86%) and specificity (77%) for diagnostic accuracy.

Researchers also found that the lower the alpha-synuclein level, the higher (worse) the NMSS total score and single-item 3 scores, which refer to mood/cognition, and item 9 scores, referencing pain/smell/weight/sweating. This association was independent of age, disease duration, motor impairment severity and dopaminergic treatment, and indicates prominent dysfunction of brain networks controlling these functions, the scientists observed.

A similar inverse association was found between phosphorylated tau level and NMSS total score and item 3 score, though in this case it was not statistically significant. Alpha-synuclein level was not significantly associated with motor symptoms assessed with the UPDRS 2-3.

“We suggest that the decrease of CSF a-syn levels mirrors a widespread degenerative process involving non-dopaminergic networks,” the researchers wrote.

Although cautioning that the results are preliminary and need validation in longer studies, the team believes that “measurement of total CSF [alpha-synuclein] may represent a biomarker for NMS [non-motor symptoms], supporting the assessment of frailty in PD [Parkinson’s disease] patients.”

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Specific Biomarkers May Help to Distinguish Parkinson’s Dementia from Dementia with Lewy Bodies

biomarkers, dementia study

The levels of specific protein biomarkers in the cerebrospinal fluid (CSF) — the liquid surrounding the brain and spinal cord — can distinguish patients with Parkinson’s disease dementia (PDD) from those with dementia with Lewy bodies (DLB) regardless of dementia stage, according to a new study.

The research, “Cerebrospinal fluid markers analysis in the differential diagnosis of dementia with Lewy bodies and Parkinson’s disease dementia,” appeared in the journal European Archives of Psychiatry and Clinical Neuroscience.

Brain protein clumps known as Lewy bodies are characteristic of both Parkinson’s and DLB.

Current practice gives a DLB diagnosis if dementia occurs before or during the first year of parkinsonism, a general term for neurological disorders that cause movement problems similar to those of Parkinson’s patients.

As such, a follow-up is essential to differentiate between PDD and DLB. However, the overlap of clinical symptoms and the difficulty in establishing when specific symptoms start make this distinction challenging and impacts treatment.

A percentage of DLB cases share a varying extent of pathological features with Alzheimer’s. But, unlike in that disease, no specific CSF biomarkers  have been validated for DLB and PDD. Researchers, for this reason, assessed the diagnostic potential of widely accepted CSF biomarkers across dementia stages to differentiate between DLB and PDD.

A total of 136 patients, all being treated at University Medical Center, Göttingen, Germany, underwent routine laboratory testing and a spinal tap to collect CSF. Cognitive examinations were preformed using the Mini-Mental State Exam (MMSE), and 65% of these patients were also tested with the Montreal Cognitive Assessment (MoCA), and the Clinical Dementia Rating (CDR).

The group included 51 people (31 men) with a diagnosis of probable DLB — 6 later confirmed — 53 with Parkinson’s, and 32 who were cognitively intact. Thirty-one of the Parkinson’s patients met the criteria for PDD (16 women and 15 men). Patients exhibiting dementia were classified as mild, moderate or severe.

CSF samples were tested for the proteins amyloid-beta1–42, tau, phoshorylated tau (a modified form of the tau protein), neuron-specific enolase (NSE) — a predictor of severity and neurobehavioral outcome after acute stroke, and implicated in Alzheimer’s — and S100B, a marker of brain damage. Of note, both amyloid-beta and phoshorylated tau form clumps in the brains of Alzheimer’s and Parkinson’s patients.

Levels of tau and amyloid-beta1–42, as well as the phosphorylated tau/total tau ratio were helpful in distinguishing between DLB and Parkinson’s patients with or without dementia.

Specifically, tau levels were higher in DLB than in Parkinson’s patients regardless of cognitive status, and were also higher in Parkinson’s patients with dementia than those without it.

DLB patients had lower levels of both amyloid-beta1–42 and phosphorylated tau/total tau ratio than did Parkinson’s dementia patients. This ratio was lower in DLB patients with mild and moderate dementia.

Levels of tau and phosphorylated tau protein in patients’ CSF reflected the severity of dementia in both DLB and PDD patients. Tau ratio enabled a distinction between Parkinson’s patients with mild and moderate dementia, and was lower in those with severe dementia than those with mild dementia.

Lower levels of amyloid-beta1–42 correlated with a rapid disease course in DLB but not in PDD. Both DLB and Parkinson’s patients with dementia showed elevated levels of S100B in comparison to healthy controls — indicating brain damage.

For both DLB and PDD, patients with less than a year of disease duration showed a trend toward higher tau, phosphorylated tau and NSE as opposed to lower amyloid-beta1–42  when compared to those whose disease had been diagnosed earlier.

Nevertheless, only values for amyloid-beta1–42 were lower in DLB patients whose dementia was confirmed less than one year after their primary diagnosis, compared to those diagnosed with PDD.

“These results have clinical relevance by suggesting that the descent of CSF [amyloid-beta1–42] values mainly in rapid disease course might have a prognostic significance,” the researchers wrote.

“[W]e conclude that CSF profile with the appropriate clinical context could be effective in distinguishing DLB from PDD patients, regardless of the severity of dementia,” they added.

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Source: Parkinson's News Today