Projects

Amyloid-β accumulation: the role of Ubiquitin C-terminal hydrolase L1 (Uch-L1)
2015 | Grant Fondazione Veronesi - Michela Guglielmotto

Alzheimer’s disease (AD) is the most common age-related disorder that results in the loss of memory and cognitive functions. Accumulation of amyloid-β peptides (Aβ), the main components of senile plaques, in the brain represents the key pathological event of AD (Selkoe, 2001). Aβ results from two sequential endoproteolytic cleavages operated on the amyloid-β precursor protein (AβPP) by β-secretase (BACE1) and γ-secretase.

Oxidative stress together with important oxidative stress-related risk factors connected to AD such as hypoxia, hyperglycemia and hypercholesterolemia, are the potential causes of the increased BACE1 activity. Recently it has been demonstrated that the link between stroke, brain ischemia, and AD is hypoxia, the direct consequence of cerebral hypoperfusion. Indeed, hypoxia increases BACE1 expression and activity, resulting in Aβ overproduction, as it has been shown  in vitro  as well as in AD transgenic mice.

This project aims to expand the knowledge gathered by our previous results. We demonstrated that hypoxia, both  in vitro  and  in vivo  , up-regulates BACE1 mRNA expression in a biphasic manner. Also, we showed that Aβ1-42 down-regulates the activity of ubiquitin C-terminal hydrolase L1 (Uch-L1) and that this event is associated with BACE1 up-regulation owing to a transcriptional effect and to an impairment of its lysosomal degradation.
Uch-L1 is an abundant neuronal enzyme , involved in either the addition or the removal of ubiquitin from proteins that are destined to be metabolized via the ATP-dependent proteasome pathway.

On these bases, we aim to demonstrate:

• if the Uch-L1 inhibition can be found in different models of brain injury related to AD pathogenesis such as hypoxic and ischemic injury and
• if this decrease could be a mechanism leading to an up-regulation of BACE1 and a Aβ overproduction, with consequent neuronal cell death.