Abstract
Amyloid-β (Aβ) misfolding is one of the hallmark pathological features of Alzheimer’s disease (AD). AD can manifest with diverse symptomatology including variable rates of cognitive decline, duration of clinical disease, and other detrimental changes. Several reports suggest that conformational diversity in misfolded Aβ is a leading factor for clinical variability in AD, analogous to what it has been described for prion strains in prion diseases. Notably, prion strains generate diverse patterns of misfolded protein deposition in the brains of affected individuals. Here, we tested the in vivo prion-like transmission features of four AD brains displaying particular patterns of amyloidosis. AD brains induced different phenotypes in recipient mice, as evaluated by their specific seeding activity, as well as the total amount of Aβ deposited surrounding vascular structures and the reactivity of amyloid pathology to thioflavin S. Our results support the notion that AD-subtypes are encoded in disease-associated Aβ. Further research exploring whether AD include a spectrum of different clinical conditions or syndromes may pave the way to personalized diagnosis and treatments.
Highlights
Alzheimers disease (AD) is a heterogeneous and multifactorial brain disorder and the most common form of dementia in elderly population
Our results suggest that different arrangements of misfolded Aβ template the propagation of unique pathological features associated with AD
AD60649 sample displayed abundant Aβ deposition albeit the majority of aggregates observed in this patient were less compact as the ones observed in sample AD60129 while displaying abundant diffuse Aβ plaques (Fig. 1c)
Summary
Alzheimers disease (AD) is a heterogeneous and multifactorial brain disorder and the most common form of dementia in elderly population. AD is characterized by progressive neuronal degeneration, leading to severe cognitive impairments [1, 2]. The most prominent pathological hallmarks of AD are the extracellular deposition of amyloid-β (Aβ) peptides in the form of plaques and the intracellular accumulation of hyper-phosphorylated Tau (p-Tau) protein as neurofibrillary tangles [3]. Aβ accumulation follows a sequential/ progressive anatomical distribution that is initiated in the neocortex and subsequently expands to allocortical regions, striatum, brain stem and cerebellum [11].
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