De novo induction of amyloid-β deposition in vivo

Abstract

Alzheimer's disease (AD), the most common type of senile dementia, is associated to the build-up of misfolded amyloid-β (Aβ) in the brain. Although compelling evidences indicate that the misfolding and oligomerization of Aβ is the triggering event in AD, the mechanisms responsible for the initiation of Aβ accumulation are unknown. In this study, we show that Aβ deposition can be induced by injection of AD brain extracts into animals, which, without exposure to this material, will never develop these alterations. The accumulation of Aβ deposits increased progressively with the time after inoculation, and the Aβ lesions were observed in brain areas far from the injection site. Our results suggest that some of the typical brain abnormalities associated with AD can be induced by a prion-like mechanism of disease transmission through propagation of protein misfolding. These findings may have broad implications for understanding the molecular mechanisms responsible for the initiation of AD, and may contribute to the development of new strategies for disease prevention and intervention.

Cross-Fertilization of Studies in Neurodegeneration

“…Low age at exposure and an inverted V-shaped susceptibility function are supported by epidemiologic observations of childhood age at whooping cough epidemics and PD in Iceland, Creutzfeldt-Jakob disease accidentally transmitted by growthhormone treatment, and dietary exposure to bovine spongiform encephalopathy, as well as age at surgery and risk of sporadic CJD at least 20 years later. The relevance of driver 1 for PD and AD is supported by multiple experimental data relating to: (a) the potential host-tograft induction of AS degeneration from patients diagnosed with PD who received tissue grafts, and disease induction by seeding in the AS and tau mouse models [3,4]; (b) the age-at-exposure-related effect on neurodegeneration induced by neurotropic agents [5,6]; (c) the fact that intracerebral injection of brain extracts containing aggregated AS into young AS-transgenic mice stimulates the formation of AS lesions in the host [7]; and, (d) a similar feature displayed by the male-mouse castration model of PD, which is only efficient when castration is performed on 4-6 week old mice [8]. With regard to this driver, we wonder whether the authors explored a similar experimental approach with younger rats exposed to E. coli curli, with different or clearer results.…”

Alzheimer's Disease and Prion Protein

“…Local injection of misfolded Aβ in the brains of AD transgenic mice has been found to trigger the misfolding and spreading of otherwise normal Aβ throughout the brain, indicating the prion-like activity of Aβ (108)(109)(110)(111)(112)(113)(114). Injection of AD brain extracts into the hippocampus of mice expressing human wild-type APP induces Aβ deposition, which progressively increases over time after inoculation and spreads to brain areas far from the injection site, where other Aβ-related pathology is also observed (114). It is believed that certain Aβ conformations tend to self-propagate, and targeting those specific Aβ assemblies may interrupt the spread of Aβ deposition, hence exerting therapeutic effect on AD (109).…”

“…Thus, a prionbased mechanism is proposed to unite a wide array of neurodegenerative diseases, all of which may stem from misfolded proteins self-propagating through the brain (103,108). Local injection of misfolded Aβ in the brains of AD transgenic mice has been found to trigger the misfolding and spreading of otherwise normal Aβ throughout the brain, indicating the prion-like activity of Aβ (108)(109)(110)(111)(112)(113)(114). Injection of AD brain extracts into the hippocampus of mice expressing human wild-type APP induces Aβ deposition, which progressively increases over time after inoculation and spreads to brain areas far from the injection site, where other Aβ-related pathology is also observed (114).…”

On the issue of transmissibility of Alzheimer disease

“…3 This implies that AD might harbor the potential for being communicable. Latest experiments of Jucker, Eisele and collegues, 4 Morales et al 5 as well as Clavaguera et al 6 have shed new light on the possibility that certain neuropathological hallmarks of AD such as Aβ or tau aggregation might be inducible. However, the results of these experiments have to be interpreted with care and cannot be generalized since they were performed using highly susceptible mouse models.…”

“…[27][28][29] Morales and colleagues took a further step and were able to show that this process is reproducible in animals, which without inoculation, would not develop Aβ plaques. 5 It is hypothesized, that some kind of cell-to-cell transfer of pathogenic Aβ molecules must have been present in this scenario. The results of various immunization studies could be used as an argument in favor of this cell to cell transfer.…”