Disruption of a specific molecular pathway may lead to the degeneration seen in late-onset Alzheimer’s disease, the non-familial and most common form of the disorder. A team headed by NIA scientists found when a signaling pathway called ApoER2-Dab1 malfunctions in human brain neurons, the neurons accumulate phosphorylated tau — the form that leads to tau tangles — and die during the earliest stages of Alzheimer’s. The findings, which were published in Acta Neuropathologica Communications, provide a better understanding of the origin of the disease and possible therapeutic targets.
The protein apolipoprotein E (APOE), which is involved in transporting cholesterol and other fat in the body, binds to several receptors, or small molecules, that occur in or on cells. The researchers determined neurons that accumulate tau in early Alzheimer’s have one of these receptors, APOE receptor 2 (ApoER2), on their surface. But researchers still didn’t know why these neurons degenerate in late-onset Alzheimer’s, while other neurons did not.
Studies from other scientists showed that ApoER2 was part of a complex signaling system called ApoER2-Dab1, which regulates memory, cognition, and neuronal integrity using a four-pronged mechanism. Scientists in this study knew that during Alzheimer’s, several proteins that make up this multi-arm mechanism tended to accumulate in certain parts of the brain.
Using advanced microscopy techniques that were developed through an NIA and National Institute of Neurological Disorders and Stroke collaboration, the research team labeled 80 different proteins in postmortem brains from individuals with Alzheimer’s. These protein markers enabled the team to see exactly where each protein accumulated.
The researchers found that five neuron populations that accumulate tau in the earliest stages of Alzheimer’s have lots of ApoER2 on their surfaces and that tau is only one of many ApoER2-Dab1 proteins that accumulate during the disease. APOE, beta-amyloid, and other proteins associated with Alzheimer’s also build up in these neurons. The data suggests the destabilization of the ApoER2-Dab1 pathway is a plausible, alternative explanation for why specific neurons degenerate in Alzheimer’s.
This research is related to NIA’s AD+ADRD Milestone 2.E, “Create cross-disciplinary research programs aimed at understanding the integrative physiology of APOE and its pharmacogenetic effects on various pharmacological and non-pharmacological interventions.”
This research was supported by the NIA Intramural Research Program and NIA grants ZIAAG000453, P30AG019610, and P30AG072946.
Reference: Ramsden CE, et al. ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer’s disease. Acta Neuropathologica Communications. 2023;11(1):197. doi: 10.1186/s40478-023-01693-9.
