Transmissibility of amyloid-Beta misfolding: Induction of A-Beta amyloidogenesis

Alzheimer's disease (AD) is the most common type of dementia in elderly people. Clinically, AD is principally characterized by impairments in memory and cognition. Currently, there is no effective treatment for this disorder. Since more than 95% of AD patients are currently classified as “sporadic”, it is important to understand the etiology of this disease. The main histopathological feature of AD includes the presence of cerebral deposits of fibrillar aggregates consisting mainly of amyloid-β protein (Aβ). Aβ aggregates have been extensively studied, and are considered the main responsible for triggering the pathological events observed in this disease. Interestingly, misfolding and aggregation of proteins are the predominant pathological condition in several other diseases known as Protein Misfolding Disorders (PMDs). PMDs include AD and prion diseases, among many others. The latter are characterized by unique transmissible features. Recently, we and others have demonstrated that Aβ aggregation can be induced in a prion-like manner in animals intra-cerebrally injected with brain preparations from patients affected by pathologically and clinically confirmed AD, suggesting that this disease may have a transmissible origin. Nevertheless, it remains to be demonstrated if this phenomenon can occur under more realistic and medically relevant condition. My Ph.D. project focused on the evaluation of whether AD pathological abnormalities could be accelerated in vivo by blood transfusions, a common practice in medical care. Our results showed that transfusion of blood from aged transgenic mouse models of AD accelerates Aβ deposition and associated neurological and behavioral alterations emulating what is reported in the transmission of prion diseases by blood transfusions. Little is known about the transmission potential of samples derived by mild cognitive impairment (MCI) patients (which is considered as an earlier stage of AD), or aged asymptomatic individuals containing Aβ aggregates in their brains (here referred as Non-Demented with Alzheimer’s disease Neuropathology or NDAN). We found that brain samples coming from MCI and NDAN induced an AD-like pathology in the brain of injected mice. Our results suggest that the sole presence of Aβ aggregates, regardless of the presence of clinical signs, is necessary to induce Aβ deposition in mice. In order to associate amyloid induction with the presence of misfolded Aβ structures, we evaluated the Aβ seeding capability of AD samples depleted of Aβ aggregates. We found that animals inoculated with the aggregate-depleted sample showed lower amount of Aβ aggregates in their brains compared to non-treated AD brains, suggesting that depletion of biologically active Aβ seeds reduced Aβ seeding capability in transgenic mice. Research on AD transmissibility could be useful in order to explain how disease progresses in the brain, the appearance of some sporadic cases, and to develop new therapeutic strategies for the treatment of this devastating pathology.