Research

Molecular and Cellular Biology of Alzheimer's Disease

Neurodegenerative diseases are acquired or inherited disorders of the central nervous system, typically showing progressive neuronal loss in specific human brain regions. Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. Although the etiological factors that cause the onset of AD remain to be defined, a great number of studies have shown that the presence of senile or neuritic plaques in human brains is one of the pathological hallmarks of AD. Neuritic plaques consist mainly of amyloid deposition surrounded by dystrophic neurites, reactive astrocytes and activated microglial cells.

The major component of amyloid plaques is β-amyloid (Aβ), which is excised from amyloid precursor protein (APP) through sequential cleavages by β-secretase and gamma-secretase. Our group was one of the first to report the molecular identification of β-secretase, also called BACE1 as an acronym (Yan et al., 1999). Studies have demonstrated that inhibition of BACE1 activity or reduction of BACE1 levels in vivo dramatically reduces production of Aβ, which is widely believed to be the primary culprit in Alzheimer’s pathogenesis. Our ongoing projects include further investigations into the biological functions of BACE1 as well as understanding the modulation of BACE1 by cellular factors. We have recently identified reticulon/Nogo proteins (RTN) as negative modulators of BACE1 (He et al., 2004). Further characterization of RTN proteins is under active investigation. 

Characterization of BACE1 knockout mice has now allowed us to reveal additional functions of BACE1 in vivo. In BACE1–null mice, the process of myelination is delayed and myelin thickness is markedly reduced, indicating that genetic deletion of BACE1 causes hypomyelination (Hu et al., 2006).  Biochemical studies reveal an altered neuregulin/Akt signaling pathway in BACE1–null mice. We have shown that full–length neuregulin–1 is increased and its cleavage product is decreased in the CNS of BACE1–null mice. These findings have led us to postulate that neuronal–enriched BACE1 cleaves neuregulin–1, and also that processed neuregulin–1 regulates myelination via phosphorylation of Akt in myelin–forming cells. This discovery has opened a new avenue for us to study how BACE1 regulates myelination during development and remyelination in adults and how cleavage of neuregulin-1 by BACE1 participates in this regulation.

The presence of dystrophic neurites, which usually surround the core amyloid deposition, is considered to be an important pathological feature in AD brain.  We found that RTN3, a member of the reticulon/Nogo family, is not only greatly accumulated in dystrophic neurites but also plays a role in their formation (Hu et al., 2007). Transgenic mice overexpressing RTN3 produce RTN3-immunoreactive dystrophic neurites (RIDNs) in the absence of amyloid deposition and neurofibrillary tangles. More importantly, we showed that RIDNs are naturally formed in aged mouse brains and that the occurrence of RIDNs in mice causes reduced long term potentiation (LTP) and spine density as well as impaired learning and memory (Shi et al., 2009a). Thus, our transgenic mouse model expressing RTN3 can mimic and accelerate the formation of RIDNs. This unique animal model will be further investigated in order to better understand how RIDNs are abundantly formed in brains of AD patients. In addition, we have generated RTN3 knockout mice and these mice will be particularly useful to elucidate the function of RTN3 in vivo.