While amyloid proteins such as amyloid β (Aβ),α-synuclein, tau, and lysozyme are known to be prion-like; emerging data have revealed that they are also able to seed the misfolding of prion-like proteins differing in sequence. In the present study, we have developed a tool designed to test neurohistochemical outcomes associated with the entry of an amyloid protein into heterotypic neurons, i.e., neurons that do not express the invading amyloid and, instead, endogenously express amyloids differing in sequence. The stereotaxic introduction of Aβ into the rodent tegmental area of the mid-brain revealed that the foreign amyloid had infiltrated into nigral neurons. Furthermore, Aβ was found colocalized with α-synuclein, an amyloid endogenous to the substantia nigra and differing in sequence relative to Aβ. Disruption of α-synuclein status in the substantia nigra is associated with Parkinson's disease onset and progress. In addition to the study findings, a significant inroad to future neurodegenerative research was made via the stereotaxic introduction of the foreign amyloid. This technique limits the presence of confounding neurometabolic variables that may be prevalent in transgenic animal models of cross-toxicity and, thereby, better addresses the role of individual neuronal factors in cross-toxicity. Finally, the data from this work may help reconcile the high frequency of clinical comorbidity seen in neurodegenerative diseases.
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