Patterson 2019 / SNCA BAC tg mouse / Bru 2013 #1370 row tail, spreading-models comparison table (PFF vs AAV with mechanism / Tx aims / Chung 2019 paragraph), Rey 2019 / 2018 / 2016 olfactory-bulb PFF rows, PFF preparation start

Spreading-models row continuation (PFF + AAV characterization)

		tag	Mechanism	Spreading where?	주된 injection site	Contralateral transmission?	# synap injection	# injection in human	IV injection mice
PFF, Good summary in (Polinski, 2021 #1768)	Milder (vs AAV model)		aSyn PFF convert the endogenously expressed a-Syn into pathological aggregates 즉 주로 endogenous aSYN을 증식시킴	Retrograde transport: striatal injection → SN → (이후 장시간) → The anterior olfactory nucleus, motor, cingulate, piriform, prelimbic, somatosensory, motor cortex, entorhinal, and insular cortices, amygdala, ie), Neurons within these regions directly innervate the striatum (Wall et al., 2013) and the results do not support additional spread or second order propagation 즉 one synapse away만!	Striatum (쉬워서 Sortwell도 striatum 에 한다는 듯)	No fos spread
	Intervention timing		Tx aims		positive: PD 발현이전 사용 단순 모델 (Volpicelli-Daley et al. 2016)
			- aSyn prevention of aggregation - Clear aSyn deposits (before degeneration) - the latest critical timeframe to examine therapies that may provide neuroprotection from inclusion-associated degeneration		In contradiction (전체경 후 너무 짧으니), 전형적인 (eg, FFP) 모델에서, 6개월간 PFFs Recovery (Volpicelli-Daley, 2014; recent paper PMID 25166614)
{Chung 2019} Since it is well established that unilateral injections of PFFs can produce bilateral pathology, it is not possible to use the contralateral side as an internal control.18,20,39 Moreover, it is a great challenge to maintain the rPF model considering that the experiments often take months to complete.34 The variations in the implementation of the experiments, including monomer preparation, the generation of PFF seeds, and the amount of injected PFFs can also affect the consistency of the results.
AAV	Sledgehammer, 이 모델에서 neuroprotection 보이면 대단한 것임.		주로 exogenous aSYN을 증식시킴	anterograde transport만: SN→ striatal No transsynaptic transmission! (Pinto-Costa, 2023 #2714) throughout brain and contralateral 로도 간다는 듯.	SN (retrograde transmission from striatum 안 하니까)	a-syn pathology restricted to neurons transduced by AAV a-Syn pathology (Gómez-Benito 2020 #2528) predominant in pyramidal neurons (Koprich et al. 2011; Decressac et al. 2012; Lo Bianco et al. 2002), pathology in pyramidal neurons appear to diffuse along the axons to other non-transduced neurons that have not received α-syn pathology. Good model for target engagement of endogenous α-syn.

Olfactory-bulb PFF rows

	injection material	recipient	results / notes
(Rey 2019)	Pff, riboons, olfactory bulb	WT Mouse,	Spreading: SN X Striatum o Inclusions are Thioflavins-S-positive nuclear inclusions in dopaminergic neurons over weeks [26]. When injected into the substantia nigra of rats, Ribbons did not induce abundant inclusions there [38] in contrast to PFFs (47), but the injection of Ribbons did not induce loss of dopaminergic neurons in the substantia nigra of WT rats (47).
(Rey 2018)	Pff, , olfactory bulb	WT Mouse,	We recently demonstrated that injection of human α-synuclein PFFs into the olfactory bulb of wild-type mice α-synuclein fibrils recruited endogenous α-synuclein into pathological aggregates that spread transneuronally to over 40 other brain regions and synapses over 12 months. Here, t between 12 and 18 months, there is a marked increase in the number of brain regions exhibiting pathology after human, and to a lesser extent mouse α-synuclein fibril injections. At both 18 and 23 months after injection of mouse and human α-synuclein fibrils, we observed a reduction in the density of α-synuclein aggregates in some brain regions compared to others at 12 months. At 23 months, no additional brain regions exhibited α-synuclein aggregates compared to earlier time points. In addition to addressing the demonstrate that the induced α-synucleinopathy triggered a significant early neuron loss in the anterior olfactory nucleus. By contrast, there was no loss of mitral neurons in the olfactory bulb, even at 18 month post injection. We speculate that the lack of continued progression of α-synuclein pathology is due to convergence of the neural circuitry, consequential to neuron loss and possibly to the activation of pathologic responses in resilient neurons that counterbalances the gradual progression of the toxicity by the spreading α-syn.
(Rey 2016)	Pff (human and mouse-derived), olfactory bulb	WT Mouse, Approximately 40% of noradrenergic neurons located in the LC project to the OB (Doty, 2003); 0.5% of neurons from the RN and 3% of nigral dopamine neurons project to the OB in rats (Doty, 2003; Höglinger et al., 2015)	injected α-syn fibrils accumulated steadily in the OB neurons over several months, mostly initially in the olfactory bulb and then in interconnected regions. Notably, we found that PFF injection in mice systematically modified α-syn that in Thioflavin S positive, indicative of amyloid fibrils. The spreading α-syn pathology induces progressive and specific olfactory deficits in animal model of Prodromal PD and Finally, at the 12-mo time point, HuPFFs-induced PSer129 pathology was even more widespread. Cortical associative and secondary cortical brain regions (secondary visual (V2) and somatosensory (S2) cortices and the anterior cingulate area (ACG)) exhibited pathology (Figs 2 D and 3). Occasionally, we found PSer129 immunoreactivity in the locus coeruleus (LC), the substantia nigra (SN) and the medial and dorsal raphe nuclei (RN). Measurements of mitral cell density in the OB reveal no neuronal loss (Figs 1 H and I). [HuPFF vs mPFF rats] At 6 mo, we observed PSer129 pathology in areas located two synapses away from the OB, but for HuPFFs-injected mice it was restricted to ipsilateral external cortex (EC) and contralateral OB (Fig. 4 C). Finally, at the 12-mo time point, HuPFFs-induced PSer129 pathology tended to additional brain regions, some located two synapses away from the OB but particularly was less pronounced (Fig. 4 D) compared with mPFFs-injected mice (Fig. 2 D). The limited amount and spread of pathology in the HuPFFs mice

PFF preparation

	content
(Chung, 2019 #2681) good review	Validations of homemade or purchased monomeric α-syn proteins are crucial since not all α-syn monomers can aggregate and not all α-syn aggregates induce pathology
	newly established protocol from the Michael J Fox Foundation for Parkinson’s Research involves 3 stages for the proper preparation of α-syn PFFs from monomeric: 1) the preparation of the monomers, 2) the generation of PFFs from monomers, and 3) the preparation of PFF assessment is centrifuged the monomeric is segmented, and the protein concentration is measured. A portion of the starting monomers is retained for use as a negative control