Molecular approaches to the treatment, prophylaxis, and diagnosis of Alzheimer's disease: possible involvement of HRD1, a novel molecule related to endoplasmic reticulum stress, in Alzheimer's disease.

Endoplasmic reticulum (ER)-associated degradation (ERAD) is a protective mechanism against ER stress in which unfolded proteins accumulated in the ER are selectively transported to the cytosol for degradation by the ubiquitin-proteasome system. We cloned the novel ubiquitin ligase HRD1, which is involved in ERAD, and showed that HRD1 promoted amyloid precursor protein (APP) ubiquitination and degradation, resulting in decreased generation of amyloid β (Aβ). In addition, suppression of HRD1 expression caused APP accumulation and promoted Aβ generation associated with ER stress and apoptosis. Interestingly, HRD1 levels were significantly decreased in the cerebral cortex of patients with Alzheimer's disease (AD), and the brains of these patients experienced ER stress. Our recent study revealed that this decrease in HRD1 was due to its insolubilization; however, controversy persists about whether the decrease in HRD1 protein promotes Aβ generation or whether Aβ neurotoxicity causes the decrease in HRD1 protein levels. Here, we review current findings on the mechanism of HRD1 protein loss in the AD brain and the involvement of HRD1 in the pathogenesis of AD. Furthermore, we propose that HRD1 may be a target for novel AD therapeutics.