Table 1.

Function of Mature miRNAs of pri-miRNA Transcripts Differentially Expressed in Aging SVZ and 5XFAD Cortex.

Tissue	miRNA	Cell types with DE of the pri-miRNA transcript in Aged SVZ compared to Young SVZ	Cellular Processes and Gene Targets
SVZ	miR-21a	↓Expression: All cell types	Increases neurogenesis (Ma et al., 2019), found to be associated with the aging mouse (Kim et al., 2017)
	miR-99a	↓Expression: Neuron, Immature Neuron, Astrocyte2, NSC, OPC and COP, MFOL1, MFOL2, Microglia, Immune Cells, Vascular Endothelium	Decreases mTOR expression (Tsai et al., 2018). Likely involvement in commitment of progenitors to glial lineage (Stevanato and Sinden, 2014).
	miR-24–1	↓Expression: Immature Neuron	Knockout of this cluster leads to decreased NAD and other glycolytic metabolites (Jiang et al., 2021). Impaired glycolysis prevents neuronal differentiation and maturation (Agostini et al., 2016). Furthermore, this cluster is increased in terminally differentiated cells (Lal et al., 2009).
	miR-27b	↓Expression: Immature Neuron	Mir27b targets AMPK (Wang et al., 2019b). Increases in AMPK are associated with aged hippocampal NSCs and their decline (Wang et al., 2019a). Knockout of this cluster leads to decreased NAD and other glycolytic metabolites (Jiang et al., 2021). Impaired glycolysis prevents neuronal differentiation and maturation (Agostini et al., 2016) Furthermore, this cluster is increased in terminally differentiated cells (Lal et al., 2009).
	miR-23b	↓Expression: Immature Neuron	Knockout of this cluster leads to decreased NAD and other glycolytic metabolites (Jiang et al., 2021). Impaired glycolysis prevents neuronal differentiation and maturation (Agostini et al., 2016). Furthermore, this cluster is increased in terminally differentiated cells (Lal et al., 2009).
	miR-100	↓Expression: Astrocytel, MFOL1, Immune cells	Mir100 activates the innate immune response resulting in activated microglia and neurodegeneration (Wallach 2021, Chawla 2016).
	Let-7a	↓Expression: Astrocyte1, MFOL1, Immune cells	Let7a activates the innate immune response by acting as a TLR7 ligand (Nazmi 2014). Involved in neuroinflammation through microglia polarization (Yang 2018).
	miR-219a-2	↓Expression: Astrocyte2,	Increases myelination and re-myelination as well as increasing OPC differentiation (Dugas et al., 2010; Wang et al., 2017; Osorio-Querejeta et al., 2020; Brandi et al., 2021). Decreased levels have been described in neurodegenerative diseases such as MS and AD (Bruinsma et al., 2017). In AD models, it has been shown that miR-219a can regulate tau expression (Arnes et al., 2019).
	miR-338	↓Expression: Astrocyte1, Astrocyte2, NSC, Ependymal Cell,	Knockout of miR-338 causes a worsened phenotype of dysregulated myelination of miR219 mutants (Wang et al., 2017). These miRNAs work together to induce proper myelination.
	miR-582	↑ Expression: Neuron, Immature Neuron, NSC, OPC and COP, MFOL1, MFOL2, Mature Oligodendrocyte, Microglia, Immune Cells, Pericyte, Ependymal Cell, Vascular Endothelium	Represses various target genes in the apoptosis pathway (Floyd et al., 2014).
	miR-128–2	↑ Expression: Astrocyte1, Astrocyte2, NSC, MFOL1, Mature Oligodendrocyte, Microglia	Directly targets stem cell factors such as KLF4, CSF1, NANOG, and SNAIL (Qian et al., 2012). Furthermore, it has been shown that this miRNA reduced NPC proliferation (Zhang et al., 2016). Also inhibits mTOR signaling (Chen et al., 2016).
	miR-218–2	↑ Expression: MFOL1, Microglia, Immune Cells, Vascular Endothelium	Increased expression in human Alzheimer’s Disease patients has been observed (Gugliandolo et al., 2020). Additionally, this miRNA can alter the Wnt signaling pathway leading to differentiation - an important part of neurogenesis (Hu et al., 2017).
5XFAD cortex	miR-124–1	↓Expression: L5 PT, NP, PValb, Lamp5, Immature Neuron, Astrocyte1, OPC1, MFOL1, MFOL2, MFOL3, VLMC	Targets BACE1 expression involved in Alzheimer’s Disease (An et al., 2017), and mir-124 was found to be decreased in the brains of AD patients (Smith et al., 2011). Additionally, the gene Drd2 is targeted by miR-124-1 and thus the decreased miR-124-1 expression decreases prefrontal cortex performance (Kozuka et al., 2019).
	miR-3078	↓Expression: L5 PT, NP, PValb, Lamp5, Immature Neuron, Astrocyte1, OPC1, MFOL1, MFOL2, MFOL3, VLMC	Decreased in APP/PS1 mice compared to controls (Zhang et al., 2021).

Note: Column 1 indicates the mature miRNA name for pri-miRNAs that are differentially expressed with age in the SVZ or in the 5XFAD mouse cortex that have validated target genes in the literature. Column 2 indicates the direction of miRNA differential expression as well as which cell-types are differentially expressing these miRNAs in the SVZ with age. Column 3 indicates the direction and cell-type of differentially expressed miRNA in the 5XFAD cortex compared to wild-type. Column 4 describes relevant literature on the miRNA.