To identify pathological changes in microglia and astrocytes that affect their interactions with neuronal cells leading to the progression of brain diseases.
To target those specific changes both in cell culture and animal models towards the development of new therapeutic avenues for diseases such as Alzheimer’s disease, Parkinson’s disease, and Multiple Sclerosis.
To understand how metabolic disorders affect glia cell activity resulting in degenerative brain diseases. We develop new therapeutic approaches towards metabolic disorders and test them in different models of brain diseases.
To identify the role of cellular senescence in mediating a failure of aged glia cells to support normal brain activity.
Main Projects and Publications
Targeting the role of microglia activation in Alzheimer’s disease and Parkinson’s disease.
The pathological hallmark of Parkinson's disease is intercellular inclusions termed Lewy Bodies, composed mainly of α-Synuclein (α-Syn) protein. Recent findings have shown that α-Syn can be transmitted from cell to cell, suggesting an important role of microglia, as the main scavenger cells of the brain, in clearing α-Syn. We have recently discovered that microglia bearing a Parkinson-related gene mutation (DJ-1) exhibit an impaired autophagy-dependent degradation of p62 and LC3 proteins, and that manipulation of autophagy had less effect on α-Syn uptake and clearance in DJ-1 KD microglia, compared to control microglia. Our investigation into the link between microglia bearing a Parkinson-related gene mutation, α-Syn uptake and autophagy may provide useful insights into the role of microglia in the etiology of the PD.
The cleavage of amyloid precursor protein by γ-secretase is an important aspect of the pathogenesis of Alzheimer's disease. γ-Secretase also cleaves other membrane proteins, which control cell development and homeostasis. Presenilin 1 and 2 are considered important determinants of the γ-secretase catalytic site. We investigated whether γ-secretase can be important for microglial phagocytosis of Alzheimer's disease β-amyloid. We have suggested for the first time, a dual role for γ-secretase in Alzheimer's disease. One role is the cleavage of the amyloid precursor protein for pathologic β-amyloid production, and the other is to regulate microglia activity that is important for clearing neurotoxic β-amyloid deposits. Further studies of γ-secretase-mediated cellular pathways in microglia may provide useful insights into the development of Alzheimer's disease and other neurodegenerative diseases, providing future avenues for therapeutic intervention.
Understanding pathological changes in astrocytes and microglia in aging.
Alterations in astrocyte function such as a pro-inflammatory phenotype are associated with Alzheimer’s disease (AD). We had shown impairments in the ability of aged astrocytes isolated from mice to clear and uptake amyloid-β as well as to support neuronal growth. Senescent cells accumulate with age and exhibit a senescence-associated secretory phenotype, which includes secretion of pro-inflammatory cytokines. In our lab, we predicted that with age, astrocytes in AD mice would exhibit a cellular senescence phenotype that could promote neurodegeneration. We found an age-dependent increase in senescent astrocytes adjacent to Aβ plaques in AD mice. Our results suggest an important role of astrocyte senescence in AD and its role in mediating the neurotoxicity properties of astrocytes in AD and related neurodegenerative diseases.
Screening and development of new therapy tools in Alzheimer's disease and Multiple Sclerosis
In our lab, we venture into new therapeutic avenues in the field of neurodegenerative diseases. Our previous works have contributed promising data, supported by behavioral tests as well as brain imaging, that suggests several successful immunomodulatory treatments. In the field of Multiple Sclerosis, we found that a nasally administered peptide can diminish brain lesions. In the field of Cerebrovascular Amyloidosis, we show the potential use of a macrophage immunomodulator as a novel approach to reduce cerebrovascular amyloid, prevent microhemorrhage, and improve cognition. Furthermore, we found that astrocyte senescence is featured around plaques in an Alzheimer's disease mouse model, suggesting the application of anti-senescence therapeutics.
Understanding the metabolic role of glia cells in the brain
The brain requires constant energy supply in the form of glucose for its activity. About 25% of body glucose consumption is attributed to the brain. Failure in pathways that support glucose utilization in the brain; such as the reduced sensitivity of cells to insulin, was suggested to be involved in several brain diseases. A growing number of reports suggest a strong link between such metabolic dysfunction in the brain and the development of Alzheimers disease (AD). Moreover, it has been suggested that AD is “type 3 diabetes”, since both diabetes and AD may share a common feature in the form of improper insulin signaling in cells commonly termed ‘insulin resistance’. Indeed, some ongoing clinical trials report beneficial outcomes in trials that test the utilization of drugs used for diabetes as an approach to fight AD. Nevertheless, the underlying mechanisms that are affiliated with impaired insulin signaling in the brain are currently not clear. In our lab, we are interested to examine the relationship between glia, insulin homeostasis and pathological processes associated with AD.