Aged Cattle Brain Displays Alzheimer's Disease-Like Pathology and Promotes Brain Amyloidosis in a Transgenic Animal Model.

Ines Moreno-Gonzalez,Mercedes Marquez,Marti Pumarola,Claudio Soto,Rodrigo Morales,George Edwards,Gabriel Escobedo,Claudia Duran-Aniotz

doi:10.3389/fnagi.2021.815361

Abstract

Alzheimer's disease (AD) is one of the leading causes of dementia in late life. Although the cause of AD neurodegenerative changes is not fully understood, extensive evidence suggests that the misfolding, aggregation and cerebral accumulation of amyloid beta (Aβ) and tau proteins are hallmark events. Recent reports have shown that protein misfolding and aggregation can be induced by administration of small quantities of preformed aggregates, following a similar principle by which prion diseases can be transmitted by infection. In the past few years, many of the typical properties that characterize prions as infectious agents were also shown in Aβ aggregates. Interestingly, prion diseases affect not only humans, but also various species of mammals, and it has been demonstrated that infectious prions present in animal tissues, particularly cattle affected by bovine spongiform encephalopathy (BSE), can infect humans. It has been reported that protein deposits resembling Aβ amyloid plaques are present in the brain of several aged non-human mammals, including monkeys, bears, dogs, and cheetahs. In this study, we investigated the presence of Aβ aggregates in the brain of aged cattle, their similarities with the protein deposits observed in AD patients, and their capability to promote AD pathological features when intracerebrally inoculated into transgenic animal models of AD. Our data show that aged cattle can develop AD-like neuropathological abnormalities, including amyloid plaques, as studied histologically. Importantly, cow-derived aggregates accelerate Aβ amyloid deposition in the brain of AD transgenic animals. Surprisingly, the rate of induction produced by administration of the cattle material was substantially higher than induction produced by injection of similar amounts of human AD material. Our findings demonstrate that cows develop seeding-competent Aβ aggregates, similarly as observed in AD patients.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia among elderly people and one of leading public health problems in developed countries
We investigated the presence of AD-like pathology in aged cow brains and whether, in analogy to prion diseases, Aβ aggregates derived from cattle brain can induce Aβ misfolding and aggregation in a transgenic mice model of AD amyloidosis
To examine the relative amount of amyloid deposits observed in cattle brain and compare it with that present in patients affected by AD, we performed image analysis of the temporal area from 14 old cows exhibiting amyloid pathology and five patients with AD (Figure 1C)

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia among elderly people and one of leading public health problems in developed countries. In addition to AD, various other protein misfolding diseases (PMDs) are thought to be caused by accumulation of misfolded aggregated proteins in various tissues, including highly prevalent illnesses such as Parkinson’s disease (PD), type 2 diabetes and more than 20 other diseases (Chiti et al, 2006; Soto, 2012) Among the latter, prion diseases are quite intriguing because they are transmissible by infection through a proteinaceous infectious agent known as prion (Prusiner, 1998). The molecular mechanism responsible for prion infectivity depends on the ability of the misfolded prion protein aggregates to act as seeds, inducing the templated conversion of natively folded prion protein into the developing aggregates (Soto, 2012) In this manner, the pathological protein progressively grows by recruiting more and more of the normal protein. Disease transmission has been observed even when seeds were administered systemically (Eisele et al, 2010)

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