Accumulation of saposin in dystrophic neurites is linked to impaired lysosomal functions in Alzheimer's disease brains

Neuritic plaques in Alzheimer's disease (AD) brains refer to beta-amyloid (A beta) plaques surrounded by dystrophic neurites (DNs), activated microglia and reactive astrocytes. Most recently, we showed that DNs form sequentially in three layers during plaque growth. Although lysosomal proteins such as LAMP1 are found in DNs, it is not clear how many and how early lysosomal proteins are involved in forming neuritic plaques. To answer this unmet question, we examined APP knock-in (APP(NL-G-F)), 5xFAD and APP/PS1 Delta E9 mouse brains and found that the lysosomal activator proteins saposins (SAPs) and LAMP1 were accumulated to surround A beta plaques at the earliest stage, namely the 1st layer of DNs. Noticeably, lysosomal hydrolases were not detectable in these early DNs, suggesting that DNs at this early stage likely enrich dysfunctional lysosomes. In old AD mouse brains and in the later stage of human AD brains, SAP-C+-DNs and LAMP1(+)-DNs were gradually reduced in concomitant with the growth of amyloid plaques. Remarkably, the observed LAMP1 immunoreactivity near plaques in aged AD mouse and human brains were actually associated with disease-associated microglia rather than neuronal sources, likely reflecting more severely impaired lysosomal functions in neurons. Western blot analyses showed increased levels of SAP-C in AD mouse brains, and A beta oligomers induced elevated levels of SAP-C in cellular assays. The elevated protein levels of SAP-C in AD mouse brains during plaque growth potentially contributed lysosomal membrane leakage and loss of hydrolases. Together, our study indicates that lysosomal functions are impaired by being entrapped in DNs early during plaque growth, and this may viciously facilitate growth of amyloid plaques.

Automated summary

This text highlights the accumulation of lysosomal proteins in the early stages of neuritic plaques in Alzheimer's disease brains, suggesting that dysfunctional lysosomes may play a role in the growth of amyloid plaques. The presence of disease-associated microglia near plaques in aged AD mouse and human brains may reflect impaired lysosomal functions in neurons. Increased levels of SAP-C in AD mouse brains during plaque growth may contribute to lysosomal membrane leakage and loss of hydrolases.