Evidence of intraneuronal A[beta] accumulation preceding tau pathology in the entorhinal cortex

• Published in: Acta neuropathologica Vol. 136; no. 6; p. 901
• Main Authors: Welikovitch, Lindsay A, Do Carmo, Sonia, Maglóczky, Zsófia, Szocsics, Péter, Loke, János, Freund, Tamás, Cuello, A. Claudio
• Format: Journal Article
• Language: English
• Published: Springer 01.12.2018
• ISSN: 0001-6322
• DOI: 10.1007/s00401-018-1922-z

Growing evidence gathered from transgenic animal models of Alzheimer's disease (AD) indicates that the intraneuronal accumulation of amyloid-[beta] (A[beta]) peptides is an early event in the AD pathogenesis, producing cognitive deficits before the deposition of insoluble plaques. Levels of soluble A[beta] are also a strong indicator of synaptic deficits and concurrent AD neuropathologies in post-mortem AD brain; however, it remains poorly understood how this soluble amyloid pool builds within the brain in the decades leading up to diagnosis, when a patient is likely most amenable to early therapeutic interventions. Indeed, characterizing early intracellular A[beta] accumulation in humans has been hampered by the lack of A[beta]-specific antibodies, variability in the quality of available human brain tissue and the limitations of conventional microscopy. We therefore sought to investigate the development of the intraneuronal A[beta] pathology using extremely high-quality post-mortem brain material obtained from a cohort of non-demented subjects with short post-mortem intervals and processed by perfusion-fixation. Using well-characterized monoclonal antibodies, we demonstrate that the age-dependent intraneuronal accumulation of soluble A[beta] is pervasive throughout the entorhinal cortex and hippocampus, and that this phase of the amyloid pathology becomes established within AD-vulnerable regions before the deposition of A[beta] plaques and the formation of tau neurofibrillary tangles. We also show for the first time in post-mortem human brain that A[beta] oligomers do in fact accumulate intraneuronally, before the formation of extracellular plaques. Finally, we validated the origin of the A[beta]-immunopositive pool by resolving A[beta]- and APP/CTF-immunoreactive sites using super resolution structured illumination microscopy. Together, these findings indicate that the lifelong accrual of intraneuronal A[beta] may be a potential trigger for downstream AD-related pathogenic events in early disease stages.