Alzheimer’s disease (AD) is a highly heterogeneous, multifactorial disorder, whose complex pathogenic etiology leads to neurodegenerative changes and cognitive decline. Recently, the role of the cerebral vasculature in AD has attracted much attention due to the association of vascular disease and its risk factors with cognitive impairment and AD and of the complex functional relationship between components of the neurovascular unit (NVU) in ischemia and neurodegenerative diseases. Current data show that in AD brains there is significant reduction of microvascular density, increased numbers of fragmented vessels, atrophic “string vessels” and changes of vessel diameter pointing towards endothelial dysfunction in AD. Moreover, data from animal models of AD show that vascular pathology, such as the breakdown of the blood brain barrier (BBB), occur prior to the appearance of amyloid plaques suggesting further that primary vascular pathology may be an etiological factor causing neuronal dysfunction and degeneration.

Since in the CNS neurons and endothelial cells (EC), which make up part of the NVU, work in concert to enable proper brain homeostasis and function, any detrimental events occurring within the microvasculature will affect neuronal activity and vice versa.

Interestingly mutations in presenilin 1 (PS1), which give rise to familial AD (FAD), have been shown to result in profound degeneration of brain vasculature as well as atrophy of neuronal dendrites in a mouse model harboring it.

In our laboratory we study the role of PS1 and its mutations found in FAD on brain endothelial cell function and vascular integrity and we aim to identify mechanisms through which such effects are achieved. We apply in vitro angiogenesis assays using primary endothelial cells from mouse brains and in vivo ischemia model to assess the effects of PS1 FAD mutations in the ability of the brain to resist toxic insults. We also identify changes in brain vasculature in various experimental conditions using MRI imaging, confocal microscopy and molecular biology techniques focusing on protein-protein interactions within angiogenic protein complexes in the brain.

To examine the effects of Familial Alzheimer’s disease (FAD) mutations on neurodegeneration, we study the genetics, molecular biology, and biological functions of wild type (WT) and mutant presenilins (PSs) and Amyloid Precursor protein (APP). We found that PS1 FAD mutants cause a loss of γ-secretase cleavage function at ε-sites of substrates manifested by both, decreased production of cytosolic peptides that function in cell signaling and accumulation of γ-secretase substrates. These data support a theory that PS1 FAD mutations promote neurotoxicity by inhibiting γ-secretase-catalyzed ε-cleavage of substrates thus reducing cell signaling while causing accumulation of membrane-bound cytotoxic peptides. We have also found that PS1 mediates brain-derived neurotrophic factor (BDNF)-dependent neuroprotection against toxic insults such as oxidative stress and glutamate toxicity. We currently examine the mechanisms of the PS1-dependent neuroprotection and the effects of FAD mutants on trophic factor-mediated nueroprotection of cortical neurons using both in vitro primary neuronal cultures and in vivo transgenic mouse models.

Recent reports show that progranulin (PGRN) gene null or missense mutations are linked to frontotemporal lobar degeneration (FTLD), a form of dementia characterized by severe neuronal loss in the frontal and temporal brain regions of adult patients. The nature of these mutations suggests that survival of certain neuronal brain populations need expression of both functional alleles of PGRN (haploinsufficiency). We found that PRGN stimulates phosphorylation and activation of neuronal MEK/ERK/p90RSK and PI3K/Akt cell survival pathways and rescues cortical neurons from cell death induced by glutamate or oxidative stresses. Our data showed that extracellular PRGN acts as a neuroptotective factor supporting the hypothesis that in FTLD reduction of PGRN results in decreased survival signaling and neuroprotection against excitotoxicity and other stresses, leading to accelerated neuronal death. We are currently working on the identification of receptors that mediate the cellular effects of PRGN and its mutants involved in FTLD