Amyloid Deposits in Non-Alzheimer’s Brains

Alzheimer’s shows Aβ amyloid deposits in the brains. Learn more as we analyze samples from people with mild cognitive impairment.
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Background: One of the main features of Alzheimer’s disease (AD) is the presence of Aβ Amyloid-b deposition in patients’ brains, which accumulates decades before the onset of symptoms. We and others have demonstrated that cerebral Aβ-amyloidosis can be induced in vivo by administering AD-brain extracts into transgenic mice. However, it is currently unknown whether amyloid formation can be induced using extracts from individuals harboring Aβ deposits without clinical disease.

Results: In this study, we analyzed the amyloid-inducing capability of samples from individuals affected by mild cognitive impairment (MCI) and Non-Demented persons with Alzheimer’s disease Neuropathology (NDAN). Our results show that inoculation of transgenic mice with MCI and NDAN brain samples accelerated Aβ pathology similar to extracts from confirmed AD.

Conclusions: This data demonstrates that the sole presence of Aβ aggregates in a given sample, regardless of the clinical condition, can accelerate Aβ deposition in vivo. These findings indicate that the amyloid-inducing activity may be present in people’s brains during pre-symptomatic or a-symptomatic stages of AD.

Background on Amyloid Deposits

Alzheimer’s disease (AD) is a prevalent brain disorder, mostly affecting individuals over 65.

Clinically, this progressive and irreversible neurodegenerative illness is characterized by cognitive decline, which invariably leads to dementia. The hallmark neuropathological lesions of AD brain are the extracellular deposition of misfolded amyloid-β (Aβ) as amyloid plaques and the formation of neurofibrillary tangles composed of intracellular aggregates of hyper-phosphorylated tau. Aβ aggregates in AD can be found in various arrangements such as soluble Aβ oligomers, diffuse deposits, dense core senile plaques, vascular deposits, and intracellular aggregates.

To a different degree, all these structures have been associated with cell toxicity and tissue dysfunction.

Accumulation of Aβ aggregates in the brain is thought to begin many years or even decades before the onset of AD clinical symptoms. Indeed, abundant amounts of Aβ deposits are detected in the brain of some people affected by mild cognitive impairment (MCI), which is considered a precursor stage of Alzheimer’s disease. Most amnestic MCI patients do not meet the full neuropathologic criteria for AD, but their pathological features suggest a transitional state evolving towards Alzheimer’s.

MCI is a clinical condition usually defined by subtle memory changes that do not significantly affect daily life. MCI does not meet diagnostic criteria for dementia; however, people affected by this condition are at high risk of converting into Alzheimer’s disease.

Alternatively, it is widely known that older adults usually exhibit cerebral Aβ pathology, even without any signs of dementia. In fact, it is not uncommon to find cases of aged non-demented subjects harboring abundant amyloid lesions in their brains (here referred to as Non-Demented individuals with Alzheimer’s disease Neuropathology or NDAN). These cases suggest that certain misfolded Aβ are not associated with a clinical phenotype or that some people can cope with misfolded aggregates’ accumulation.

Recent studies have demonstrated that inoculation of AD brain homogenates can accelerate amyloid de-position in AD-transgenic mice. Furthermore, AD samples can also induce de novo Aβ pathology in animal models that do not spontaneously develop this type of lesions during their whole lifespan. These findings suggest that the accumulation of Aβ deposits follows a seeding-dependent misfolding process and aggregation-induced in a prion-like manner by administering preformed aggregates. Experimental induction of amyloid pathology has been achieved by injecting brain samples from AD patients and aged AD-transgenic mice.

However, no reported studies investigate whether the pathological induction can also be observed upon inoculation of brain samples from persons at potentially pre-symptomatic or a-symptomatic stages of AD, which contain substantial cerebral amyloid deposits, but not overt dementia. In the present study, we evaluated the Aβ seeding capability of MCI and NDAN brains in AD-transgenic animals. Strikingly, we found that MCI and NDAN samples can exacerbate amyloid deposition to a similar or even greater extent than AD specimens.

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