Article from Dr. JoAnne McLaurin, PhD. Senior Scientist Sunnybrook Research Institute 2020
In 2019-2020, we have advanced one specific program more than other ongoing studies that I have previously talked about at Cryptic Rite functions. I will thus highlight our novel findings in understanding what drives the progressive loss of cognitive function in Alzheimer’s disease patients over the course of the disease and why clinical trials keep failing.
Failure of Alzheimer’s disease (AD) clinical trials, primarily those targeting amyloid, to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. A defining feature of AD is progressive accumulation of amyloid and tau pathology in the brain that ultimately leads to cognitive decline. Neuronal loss progresses across specific brain regions that interconnect with each other and is mirrored by symptomatic presentation with mild memory loss typically occurring first, followed by deficits in activities of daily living and executive function, and eventually dementia. Hippocampal dysfunction has long been thought to drive memory impairments in AD. Recently this focus has shifted to include the entorhinal cortex, a region which provides input into the hippocampus, and is affected early in AD progression. The hippocampus regulates behavioural responses to a changing environment through circuit modulatory effects. These behaviours include pattern separation and executive function as assessed by cognitive flexibility. Pattern separation involves the disambiguation between learned and novel stimuli into distinct neuronal networks, whereas executive functions consist of multiple high-level cognitive processes that drive rule generation and selection. These processes are essential to normal human behavior, and are disrupted in AD and AD models.
Thus, we utilized a rat model which recapitulates the salient hallmarks of AD pathology observed in patient populations (amyloid, tau inclusions, frank neuronal loss, and cognitive deficits). We examined the contribution of combined pathologies to cognitive function, and the effect of amyloid-attenuation in disease-bearing rats. Attenuating amyloid in disease-bearing rats rescued pattern separation and executive function. Interestingly, neither activities of daily living were rescued by attenuating amyloid. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and neuronal signature of the hippocampus. Amyloid attenuation reduced hippocampal pathology and promoted resilience in adult hippocampal neuronal function, via improvements in coupling between neuronal signals. To investigate mechanisms underlying the lack of effect on spatial memory deficits, we next examined the entorhinal cortex, a brain region whose input to the hippocampus is required for spatial memory. Reduction of amyloid in the entorhinal cortex had no effect on pathology or entorhinal-hippocampal neuronal network communication. Thus, rescue or not of cognitive function is dependent on each specific brain region’s progression of amyloid, tau and neuronal network dysfunction. Our data support the necessity for discovering early biomarkers to accurately stage disease progression, and that the use of amyloid-targeted therapeutics for clinical AD patients may be more efficient in combinatorial treatment approaches. We are now investigating the effects of combination treatments in our rodent models of AD to prove that combinations of drugs will be effective treatment options, as is seen in other complex diseases.
We continue to work on how comorbid diseases contribute to the risk of dementia and probe for novel ways to treat both the peripheral effects of comorbidities and the effects within the brain.
Article from Dr. McLaurin 2015
Dr. McLaurin has provided us with a recent article which describes more of her work and the breaktrough's she has been making! It is a large PDF file, well worth the read. Click on the link below:
Dr. McLaurin provided us with an update in December 2013 on the research being done by her and her team thanks to donations made by the CRCF Inc.
Alzheimer’s Disease Research
My laboratory has been focused on the discovery of pathways that lead to Alzheimer’s disease progression and the discovery of potential therapeutic interventions. The donations from the Cryptic Rite Charitable Foundation have helped in the understanding of two potential therapeutic strategies to treat Alzheimer’s disease, as well as present studies aimed at identifying new treatment strategies.
The first therapy that we investigated was based on the attempt to vaccinate against Alzheimer’s disease, as is done with the Poliovirus or Rubella (German Measles), to prevent Alzheimer’s disease. The target in the vaccination attempts was the toxic amyloid-beta peptide, which demonstrated efficacy in the mouse model of Alzheimer’s disease. However, this proved harmful in clinical trials of AD patients resulting in unacceptable side-effects. This strategy was not abandoned but modified from asking the body to generate an immune response to the amyloid-beta peptides to developing the antibodies in a laboratory that would function in a similar manner. Our laboratory investigated the part of the protein that was crucial for benefit in the mouse model in the hope that targeting a specific part of the protein would have increased efficacy. The verdict is still out on this type of therapy however many large pharmaceutical companies are continuing to pursue this strategy.
The second treatment strategy that we are investigating is a small molecule, scyllo-inositol, that binds to the toxic amyloid-beta protein and promotes clearance from the brain thus preventing memory loss. We tested this compound in mouse models of Alzheimer’s disease and demonstrated that treatment could both prevent and treat existing cognitive and memory deficits. We further confirmed that the memory benefits of this treatment resulted from clearance of the toxic proteins from the brain. Scyllo-inositol underwent clinical trials for treatment of mild to moderate Alzheimer’s disease under the moniker, ELND005. These trials failed to demonstrate memory and cognitive improvement in patients however it prevented the emergence of the neuropsychiatric symptoms normally associated with advancing disease. In light of these results, scyllo-inositol is being tested in clinical trials for both Alzheimer’s disease and Down’s syndrome patients to control agitation and aggression. The clinical trials are conducted by a multinational pharmaceutical company, ELAN Corporation Plc.
The clinical trials preformed to date have taught the research community that the treatment of Alzheimer’s disease will likely require drugs that target more than one pathway that is damaged in the disease progression. In light of this, our laboratory is presently trying to identify pathways that are rescued but most importantly that are not rescued after treatment with scyllo-inositol. By identifying the pathways that are not rescued, we will identify new drug targets that can either be tested with existing drugs utilized in other diseases or for development of new drugs.