Not everyone who harbors classic Alzheimer’s lesions in the brain (e.g., plaques and tangles) develops clinical symptoms of the disease. This study was designed to understand the mechanisms involved in such natural human brain resilience, as they may hold key clues for the design of novel cognitive-sparing therapies in the elderly. We are applying a revolutionary technique to expand and image the brain, with unprecedented resolution and speed, using lattice light-sheet microscopy along with a pioneering expansion microscopy (ExM) process. This technique is allowing us, for the first time, to carefully examine individual synapses in the human brain. Our work has allowed us to demonstrate that plaques and tangles do not inevitably result in neuronal and synaptic loss and impaired cognition in all individuals. We also have gained significant insight into the events that appear to be more proximate correlates to neuronal death and subsequent cognitive impairment than just the presence of plaques and tangles, including the abnormal accumulation of soluble phosphotau species in synapses and the aberrant engulfment by glial cells of those synapses. Importantly, these changes take place in the human brain even before overt neurofibrillary tangles (one of the two main brain lesions in Alzheimer’s disease brains) develop. These findings may inform the design and testing of novel meaningful therapeutic interventions for cognitive neuroprotection in the elderly.
Not everyone with a significant burden of classic Alzheimer’s disease (AD) neuropathological changes (e.g., plaques and tangles) experiences comparable cognitive decline or has the typical tissue responses of neuronal and synaptic derangement. Identifying predictive markers of such natural protection and understanding the underlying mechanisms involved may hold key clues to developing novel cognitive-sparing therapies in the elderly. This project will take advantage of a large collection of deeply characterized brains from cognitively intact individuals whose brains are free of Alzheimer’s pathology (e.g., plaques and tangles), cognitively intact individuals before death whose postmortem exam demonstrates robust amounts of plaques and tangles (“resilient”), and individuals with well-established dementia that meet pathological criteria for Alzheimer’s disease. We will use a new and revolutionary technique to expand and image the brain—with unprecedented resolution and speed—using lattice light-sheet microscopy along with a pioneering expansion microscopy process. This technique will allow us, for the first time, to visualize and analyze in the human brain the changes that take place in synapses in the setting of plaques and tangles that may be responsible for the opposite cognitive fate of resilient individuals and demented Alzheimer’s patients. We propose to test the novel idea that an aberrant microglial inflammatory response triggered by the mislocalization and accrual of toxic soluble phospho-tau species within synapses is responsible for the loss of synapses and the subsequent impairment of brain function in Alzheimer’s disease. The information derived from this project has the potential to help identify novel molecular targets that may guide the discovery of better disease-modifying treatments for Alzheimer’s disease directed at protecting the integrity of synapses and brain function, as well as the design of novel surrogate in vivo markers able to more precisely identify who among asymptomatic elderly individuals who harbor plaques and tangles in their brains will develop clinical symptoms of dementia and in what time frame. This information may provide guidance on the need and optimal timing for personalized preventive intervention.
This project will perform detailed quantitative pathologic and biochemical studies in a large series of human postmortem tissue samples to define these mechanisms, through comparisons between individuals cognitively intact at the time of death whose brains were free of substantial AD pathology at postmortem (N=54), cognitively intact individuals whose postmortem exam demonstrated significant amounts of AD changes (“resilient”) (N=59), and typical demented AD patients (N=53). The vast majority of these cases were followed prospectively for years, with extensive clinical information available and a short interval between the last detailed cognitive assessment and death, making this large set of brains unique and particularly informative.
Our previous work has allowed us to rigorously demonstrate that plaques and tangles do not inevitably result in neuronal and synaptic derangement and impaired cognition in all cases (Perez-Nievas et al., 2013). We also have gained significant insight into the events that appear to be more proximate correlates to neuronal changes and cognitive impairment than just the presence of plaques and tangles, including activation of GSK-beta enzyme and soluble phosphor-tau accrual in synapses and neuroinflammation. The identification of a histologic and biochemical “signature” characteristic of human brain resilience to AD pathology will be used to understand the hierarchy of events that results in cognitive impairment in the presence of plaques and tangles. The ultimate goal is to identify druggable pathways and molecular targets linked to brain resilience to AD pathology, and eventually to test novel meaningful interventions. We think the studies proposed here will provide valuable hints to identify novel targets and better disease-modifying treatments for AD. Given the evidence for neuroinflammation as a critical mediator in other neurodegenerative disorders, such therapies may have wide potential benefits.