Parkinson’s disease (PD) is characterized by abnormal cytoplasmic inclusions, mainly composed of misfolded α-synuclein (α-syn) [
27,
58] in neuronal soma (Lewy bodies) and neurites (Lewy neurites). α-Syn is a soluble protein, structured in α-helices when associated to membranes. Under pathological conditions it oligomerizes and aggregates into fibrils arranged in β-rich sheet structures [
16,
17,
57]. Despite the current lack of evidence that aggregated/misfolded α-syn is infectious between individuals [
35], it has been proposed that aggregated/misfolded α-syn can behave in a prion-like fashion within the nervous system of one individual. This means that aggregated/misfolded α-syn can induce the native endogenous α-syn to adopt an abnormal conformation within the same cell. The misfolded α-syn is then released into the extracellular space and is taken up by a neighboring cell. Once inside the new cell, the misfolded α-syn can seed further α-syn misfolding and aggregation. Thereby the protein acts as a template for misfolding that transmits the disease process from one cell to another. This intercellular transfer of misfolded α-syn is hypothesized to contribute to the progressive spread of Lewy pathology in the nervous system in PD and other synucleinopathies [
1,
11,
22,
30]. Earlier post-mortem studies of Lewy pathology in PD brains had led to the proposal that it gradually spreads throughout the nervous system following a predictable anatomical pattern [
6,
8]. Braak and co-workers [
5] suggested that Lewy pathology first develops in the olfactory bulb (OB), the anterior olfactory nucleus (AON), and in the dorsal motor nucleus of the vagus nerve, and based on neural connections to regions affected in later disease stages, they proposed that the pathology spread along protracted unmyelinated axons to interconnected regions. We, and others, have suggested that this spreading results specifically from axonal transport of α-syn, followed by a cell-to-cell transfer of misfolded α-syn to neighboring neurons. Numerous in vitro and in vivo studies show that α-syn can transfer between cells and seed aggregation in the recipient cell [
2,
18,
19,
25,
29,
45,
50,
62]. Notably, the slow and fast intra-axonal transport of α-syn has also been well described in vitro [
36,
56,
59], and studies using neurons in microfluidic chambers demonstrate that fibrillar and oligomeric α-syn can be taken up from the medium and transported intra-axonally in both anterograde [
25] and retrograde [
61] directions. Finally, recent studies demonstrated that α-syn aggregates appear in widespread brain areas, 1–6 months after injection of preformed α-syn fibrils into the striatum or cortex of mice [
43,
44]. This suggests axonal transport of an aggregation-prone α-syn, although it is not absolutely clear if the α-syn aggregates can transfer from one neuron to another and develop in regions that are not directly connected to the injection sites. Moreover, the ability of α-syn to spread from anatomical regions suggested to be affected early in PD to brain areas that are impacted later on has so far not been explored. With the background that Lewy pathology in olfactory structures and impairments in olfaction both appear early in PD [
20,
21], we targeted the OB. For the first time, we stereotactically injected different molecular species (monomers, oligomers composed of soluble high molecular weight species, and fibrils) of recombinant human α-syn into the OB of normal mice. We then characterized in detail the transfer of α-syn to interconnected brain regions over 72 h. Our findings indicate that α-syn monomers and oligomers are most rapidly and readily transferred from the injection site to interconnected brain regions. We observed a particular pattern of spread that matches known neural connections in the brain, but we cannot conclude with certainty that this transfer occurred by classical axonal transport. Our results supports the notion that transport of α-syn oligomers between interconnected regions might be important in the spreading of α-syn pathology between brain regions in PD.