Table 2.

SYNJ1 in cellular and murine models of Alzheimer’s disease.

Populations	Cellular and Murine Models
	Model and Treatment	Phenotype	Proposed Mechanism
Late Onset AD (LOAD)	Human APOE4/4 knock-in (KI) mouse models	SYNJ1 levels unchanged, compared to ApoE null (knock-out) mice [64] SYNJ1 mRNA levels and SYNJ1 protein levels increased, compared to APOE3/3 KI mouse models [64] miR-195 levels reduced, compared to APOE3/3 KI mice [69]	Genetically decreasing SYNJ1 levels in ApoE4 KI mice rescues the cognitive deficits exhibited by these mice [64]
	Primary cultures of hippocampal ApoE null neurons	Incubation with conditioned media derived from APOE3/3 astrocytes, but not ApoE4/4 or ApoE null astrocytes, leads to a reduction of SYNJ1 levels [64]	Accelerated degradation of SYNJ1 mRNA [64]
		Incubation with conditioned media derived from ApoE4/4 astrocytes leads to lower miR-195 levels, compared to APOE3/3 astrocytes [69]	Upregulation of miR-195 can modulate SYNJ1 expression, supported by the fact that overexpressing miR-195 reduces SYNJ1 protein levels in ApoE null, APOE3/3 and ApoE4/4 neurons [69]
	Human ApoE4/4 knock-in (KI) mouse models with or without a transgenic AD background, viral delivery of miR-195 in the hippocampus	Rescue of cognitive deficits and reduction of tau hyper-phosphorylation [69]. Reduction in Aβ42 oligomers and amyloid plaque burden in the transgenic AD background [69]
	Human iPSCs-derived neurons and astrocytes co-cultures from an ApoE4/4 LOAD patient or an APOE3/3 control.	Enlargement of lysosomes in human ApoE4/4 neurons [69]	Over-expression of miR-195 reduces lysosomal enlargement and reduces phosphorylated tau levels in human ApoE4/4 neurons [69]
	SYNJ1+/+ and SYNJ1−/− neurons co-cultured with ApoE4/4 iPSC-derived astrocytes	Reduction of lysosomal size in SYNJ1−/− neurons compared to SYNJ1+/+ neurons [69]	miR-195 acts through the control of SYNJ1 levels on lysosomal homeostasis, supported by no additional effect of over-expression of miR-195 on lysosomal size in SYNJ1−/− neurons [69]
	Tg(SYNJ1) [70], compared to WT littermates	Increased levels of SYNJ1 [52,70]
		Early endosomes enlargement [71]
		3-4-month-old: no deficit in the Morris water maze, deficit in the reverse platform test [70]	No differences in basal neurotransmission and synaptic plasticity [70]
		9-month-old: no deficit in the radial arm water maze (RAWM) and fear conditioning (FC) paradigms [52]
		19-month-old: deficit in the RAWM and decreased freezing in contextual FC [52]	Unchanged levels of pre-and post-synaptic proteins, but acute hyperexcitability and defect in the spatial reproducibility of hippocampal place fields [52]
High risk Down Syndrome (Ds)	Ts65Dn mouse model	Increased levels of SYNJ1, PtdIns(4,5)P2 reduction [70]	Restoring SYNJ1 copy number rescues PtdIns(4,5)P2 levels [70]
	Lymphoblastoid cell lines derived from individuals with DS	Increased levels of SYNJ1, enlarged early endosomes [71]	The Hsa21 segment containing SYNJ1 is sufficient to induce early endosomal enlargement [71]
	Fibroblasts derived from individuals with DS	Increased levels of SYNJ1, enlarged early endosomes [71]	Decreasing SYNJ1 levels reduces the percentage of larger endosomes [71]
	Overexpression of SYNJ1 in SH-SY5Y neuroblastoma cell lines	Enlarged early endosomes [71]
	Human iPSCs-derived neurons from individuals with DS and their euploid isogenic controls [73]	Increased levels of SYNJ1, higher secreted Aβ peptides, higher phosphorylated tau, impaired lysosomal transport, increased synaptic vesicle release [73]	Restoring SYNJ1 copy number to disomy did not rescue Aβ peptide secretion or tau phosphorylation, but restoring APP copy number did [73]
High risk Autosomal Dominant AD (ADAD)	PSEN1 and PSEN2 ADAD cells	PtdIns(4,5)P2 reduction, Aβ42 increase [74]	Similarities with the overexpression of the inositol 5-phosphatase domain of SYNJ1 [74]
	Genetic decrease of SYNJ1 in ADAD mouse models	Improvement of learning and memory deficits [75, 76]	Protection against the effect of Aβ oligomers on PtdIns(4,5)P2 decrease, long-term potentiation (LTP) impairment and synaptic toxicity [75, 77] Increased Aβ uptake and degradation [76]

Abbreviations: miR, microRNA, iPSCs, induced pluripotent stem ceils, WT, wild-type.

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