Our research programs focus on investigating the pathophysiology of Alzheimer’s disease and related dementias with the aim of discovering the cellular mechanisms and molecular pathways that are responsible for the onset and progression of these diseases. ACT is committed to translating studies of the basic biology of neurodegeneration into new therapeutics by implementing a comprehensive experimental approach which combines in vitro (primary neurons and neuronal cell lines), in vivo models of these diseases (transgenic mice), and human studies.
The neurobiology of 12/15-Lipoxygenase
The 12/15-Lipoxygenase (12/15LO) is an enzyme widely expressed in the central nervous system where its levels increase in an age-dependent manner. Previously, we demonstrated that this protein is up-regulated in brains from Alzheimer’s disease patients in specific regions known to be vulnerable to neurodegenerative insults (i.e., hippocampus and frontal cortex) and at an early stage of the disease suggesting an active involvement in its pathogenesis. In support of this hypothesis we showed that this protein acts as an endogenous regulator of Amyloid beta peptide formation by controlling APP processing via the transcriptional regulation of beta-secretase pathway via the transcription factor Sp1. Current efforts are focused on testing the hypothesis that this protein is a viable therapeutic target for Alzheimer’s disease, and investigating its functional role in the post-transcriptional regulation of tau protein and the development of its neuropathology (i.e., neurofibrillary tangles).
Diet and the risk of Alzheimer’s disease
Another area of research is the role that certain dietary factors may play in the onset of Alzheimer’s disease. In particular, we are investigating the functional role that high circulating levels of homocysteine, also known as hyper-homocysteinemia, a known risk factor for Alzheimer’s disease has on the development of its phenotype using different transgenic mouse models of the disease (i.e., the Tg2576 and 3xTg mice). These studies are designed to understand how hyper-homocysteinemia accelerates the amyloid pathology, tau hyper-phosphorylation, synaptic function, memory and learning deficits.
In addition, we are investigating the effect on brain health of one of the major component of the Mediterranean diet, which is known to have beneficial effects on human health. In particular, we have been focusing our attention on the extra virgin olive oil (EVOO) as the mediator of those benefits. By using relevant transgenic mouse models of Alzheimer’s and related tauopathies we have been studying the molecular and cellular mechanism(s) that are responsible for the beneficial effects that EVOO displays on the development of the neuropathological phenotype with particular emphasis on the autophagy machinery and its regulation.
Neuroninflammation and Neurodegeneration
Besides the accumulation of amyloid-beta peptides and highly phosphorylated tau protein deposits, substantial evidence has mounted showing that abnormal inflammatory reactions in the brain are another cardinal manifestation of Alzheimer’s disease. Leukotrienes are bioactive lipid mediators, major metabolic products of the enzyme 5-Lipoxygenase (5LO), which can trigger immune cells chemotaxis and initiate potent pro-inflammatory reactions. This enzymatic pathway is highly expressed in neurons and glial cells, and its levels are up-regulated in Alzheimer’s disease patients as well as animal models of the disease. Previously, we have demonstrated that 5LO directly modulates the development of amyloid pathology together with the behavioral deficits in these models. Current work in the lab is now focusing on its mechanistic role in regulating tau metabolism and synaptic function by implementing models that express only tau neuropathology. To reach this goal we are implementing an in vitro and in vivo approach targeting 5LO with specific pharmacological and genetic suppressor(s) and inducer(s) of this enzyme.
Environment and neurodegeneration
Emerging evidence has showed that he majority of the cases of Alzheimer’s disease and other neurodegenerative diseases are the result of a combination between genetic risk factor with environmental elements that directly influence their onset. The core of this research program is to investigate the role that environment may play in the pathogenesis of Alzheimer’s disease, tauopathies and Parkinson’s disease. To this end, we focus on chronic environmental stressors and implement different experimental paradigms in wild type as well as transgenic animal models of these diseases. In particular, we have been investigating how social isolation, circadian rhythm disruption, and sleep deprivation may induce neuropathological modification, impair synaptic function and integrity, and ultimately memory and learning deficits.
Down syndrome: Mechanisms and Pathways
Because of an extra copy of the APP gene on chromosome 21, Down syndrome individuals develop high levels of Ab peptides and Alzheimer’s disease-like brain amyloidosis early in life. By using in vitro and in vivo models of the disease, we are investigating novel pathways potentially involved in the pathogenesis of the syndrome which can eventually be tested as therapeutic targets. Further, we are interested in understanding how and if alterations in the transport and traffic system for specific proteins (i.e., APP, BACE-1) within the neurons can modulate the earliest modifications responsible for the cognitive deficits and memory impairments of the syndrome.