Paradoxical effects of mutant ubiquitin on Aβ plaque formation in an Alzheimer mouse model

Abstract

Amyloid-β (Aβ) plaques are a prominent pathological hallmark of Alzheimer's disease (AD). They consist of aggregated Aβ peptides, which are generated through sequential proteolytic processing of the transmembrane protein amyloid precursor protein (APP) and several Aβ-associated factors. Efficient clearance of Aβ from the brain is thought to be important to prevent the development and progression of AD. The ubiquitin-proteasome system (UPS) is one of the major pathways for protein breakdown in cells and it has been suggested that impaired UPS-mediated removal of protein aggregates could play an important role in the pathogenesis of AD. To study the effects of an impaired UPS on Aβ pathology in vivo, transgenic APP/PS1ΔE9 mice (APPPS1) were crossed with transgenic mice expressing mutant ubiquitin (UBB), a protein-based inhibitor of the UPS. Surprisingly, the APPPS1/UBB crossbreed showed a remarkable decrease in Aβ plaque load during aging. Further analysis showed that UBB expression transiently restored PS1-NTF expression and γ-secretase activity in APPPS1 mice. Concurrently, UBB decreased levels of β-APP-CTF, which is a γ-secretase substrate. Although UBB reduced Aβ pathology in APPPS1 mice, it did not improve the behavioral deficits in these animals.

USP14 Haploinsufficiency Ameliorates Alzheimer’s Disease-Like Pathology in APP/PS1 Mice

“…Reduction of proteasomal chymotrypsin-like activities was observed in the brain including hippocampus of AD animal models [9]. It is believed that the UPS can degrade APP proteins in the brain [10], and reduce the accumulation of extracellular amyloid proteins by regulating the production and the degradation of Aβ [11,12]. Biochemical and morphological examinations of the brain of AD patients showed that phosphorylated Tau oligomer proteins accumulated on both sides of the synapse where ubiquitinated proteins, proteasome components and related chaperone proteins were also enriched, implicating that synaptic Tau protein aberrant aggregation may be an important mediator of proteotoxicity responsible for synaptic malfunction in AD [13].…”

Mutant ubiquitin reduces Aβ plaques

“…To investigate the effects of UBB +1 expression on APP processing, we carried out secretase activity measurements on brain tissue samples from different mouse lines [ 5 ]. In APPPS1 mice, a partial decrease in γ-secretase activity was found compared to wild-type mice, in agreement with disruption of normal γ-secretase function by the PS1-ΔE9 mutation present in these animals (presenilin is the catalytic component of the γ-secretase complex).…”

“…Therefore, changes in γ-secretase activity indicated altered carboxypeptidase-like cleavage in this assay. How UBB +1 exerts this stimulating effect on γ-secretase is not clear, but a potential mechanism may involve regulation of presenilin expression [ 5 ].…”

“…In addition to the partial recovery of γ-secretase activity, protein levels of APP CTF-β (C99), as determined in immunoblots, were reduced in triple transgenes compared to APPPS1 mice ( Figure 1D ) [ 5 ]. C99 is the amyloidogenic substrate for γ-secretase, whose intraneuronal accumulation has also been suggested to be toxic.…”

“…We suggest that recovery of γ-secretase function, e.g., via stimulation of carboxypeptidase function, should be explored as a therapy to lower Aβ in AD. We did not find an ameliorating effect of UBB +1 expression on behavioral deficits in APPPS1 mice [ 5 ], but it should be noted that UBB +1 induces behavioral impairments itself [ 3 , 7 ], which could mask a beneficial effect of reducing Aβ.…”