Research

Vulnerability of Glutamatergic Neurons to Neurofibrillary Tangle Accumulation and Neurodegeneration

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and it has enormous psychosocial and economic impact on society. There is a critical need for a better molecular pathophysiological understanding of the disorder that can pinpoint novel and more effective treatment targets. Neurofibrillary tangles (NFTs), formed of abnormally hyperphosphorylated tau, have been shown to lead to neuronal death and are more closely associated with cognitive decline than amyloid plaques, another neuropathological hallmark in AD. NFTs accumulate in excitatory pyramidal neurons of the hippocampus and association neocortex. However, the molecular mechanisms mediating susceptibility of glutamatergic neurons to tau pathology and degeneration is unknown. Developing a better understanding of the molecular mechanisms causing vulnerability of excitatory neurons to damage and identifying pathways that regulate tau-mediated neurodegeneration will be essential to unraveling the pathogenesis and progression of AD and identifying potential therapeutic targets. Pereira Lab has been working on identifying key drivers of disease pathology in susceptible glutamatergic neurons using innovative sequencing technologies in mouse models of AD and human brain tissue. Gene co-expression network and key driver analyses are used, in collaboration with ISMMS Bioinformatics Department, to identify key disease drivers for experimental validation as novel therapeutic targets for AD. These projects aim to uncover novel mechanisms of disease and identification of specific therapeutic targets.

Molecular signatures of regional vulnerability to tauopathy in excitatory cortical neurons

To investigate selective regional and cellular vulnerability to tauopathy, we analyzed human post-mortem prefrontal cortex tissue from multiple tauopathies, inlucing AD, PSP, CBD and FTLD due to MAPT mutation, and found pathological tau predominantly accumulates in excitatory neurons in comparison to inhibitory neurons.

Further, using vTRAP in PS19 mice, we identified synaptic transmission and excitability changes in vulnerable neurons and brain regions, with Mef2c as a key regulator of these effects. These findings were validated in human datasets. Tau also disrupted excitatory neuron activity in the prefrontal cortex, suggesting vulnerability is likely driven by altered synaptic function and potentially due to Mef2c-mediated transcription.

Paper link: https://pubmed.ncbi.nlm.nih.gov/40481857/

Glutamate Transporter EAAT2 as a Therapeutic Target to AD

Dr. Pereira and her colleagues have previously identified the major excitatory amino acid transporter 2 (EAAT2) as a potential target to treat AD. Pereira lab members have shown in a novel EAAT2 knock-down mouse model that EAAT2 deficiency leads to accelerated age-related cognitive decline, neuroinflammation, that correlates with behavioral decline and transcriptomic overlap with human aging and AD (Sharma, Kazim et al. PNAS 2019).

Dr. Pereira and her colleagues have reported that treatment with the glutamate modulator riluzole, which has been shown to increase EAAT2 expression, can prevent age-related cognitive decline through clustering of dendritic spines, strengthening neural communication (Pereira et al, 2014). Furthermore, she has shown that riluzole rescues aging and AD-gene expression profile (Pereira et al., 2016). Recently, Dr. Pereira and her colleagues have published that riluzole prevents hippocampus-dependent spatial memory decline in an aggressive mouse model of early-onset AD (5XFAD) and reversed many of the gene expression changes in immune pathways (Okamoto et al. 2018), and specifically microglia-related genes thought to be critical mediators of AD pathophysiology, including a recently identified unique population of disease-associated microglia (DAM).

From these discoveries in her laboratory, in a highly translational approach, Dr. Pereira has designed and led a clinical trial with the glutamate modulator riluzole in patients with Alzheimer’s disease, using start-of-the art neuroimaging biomarkers (including 18F-fluorodeoxyglucose positron emission tomography -FDG-PET- and in vivo proton magnetic resonance spectroscopy -1H MRS -) along with neuropsychological testing as a potential novel disease-modifying therapy for Alzheimer’s disease. The pilot trial showed that measures of cerebral glucose metabolism through FDG-PET, a well-established Alzheimer’s disease biomarker and predictor of disease progression, declined significantly less in several pre-specified regions of interest with the most robust effect in posterior cingulate, and effects in precuneus, lateral temporal, right hippocampus and frontal cortex in riluzole-treated subjects in comparison to placebo group. Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer’s disease (2021)

Investigating Molecular Drivers of Clinical Heterogeneity in Alzheimer’s Disease

This study identifies molecular heterogeneity in tau species as a key factor in the variable progression of Alzheimer’s disease (AD). Using human postmortem brains, inferior temporal gyrus (ITG) and prefrontal cortex (PFC) brain , we found that both high- and low-molecular-weight tau, along with site-specific phosphorylation and isoform composition, influence tau seeding and rate of cognitive decline. Distinct tau strains and transcriptomic profiles linked to synaptic dysfunction and neuroinflammation suggest novel biomarkers for AD subtyping and potential targets for precision therapies.

Paper link: https://pubmed.ncbi.nlm.nih.gov/40234685/

Chronic Intermittent Hypoxia and Increased Risk to Alzheimer’s Disease

Another line of research in Dr. Pereira’s laboratory, recently funded through an R01 Award, has been to unravel the mechanisms of the effects of chronic intermittent hypoxia (CIH) that increase the risk and progression of AD pathophysiology.Pereira lab members have been generating data in animal models of AD using CIH, with very similar oxygen parameters as human obstructive sleep apnea (OSA). We have been utilizing a multi-modal and integrative approach evaluating in the setting of CIH tau pathology, regional neural network dysregulation and its underlying molecular mechanisms with innovative technologies. These studies have high translational significance to develop preventive and new therapeutic targets for AD. We have shown that CIH enhances tau seeding, propagation and accumulation and exacerbates Alzheimer-like memory and synaptic plasticity deficits and molecular signature. Chronic intermittent hypoxia enhances pathological tau seeding, propagation, and accumulation, and exacerbates Alzheimer’s-like memory and synaptic plasticity deficits and molecular signatures (2021)