Adult Hippocampal Neurogenesis in Alzheimer’s Disease: An Overview of Human and Animal Studies with Implications for Therapeutic Perspectives Aimed at Memory Recovery

Table 1

Studies investigating AHN on AD mouse models.

Mouse model	Age	BrdU treatment	BrdU	DCX	BrdU/DCX	OTHER markers	Ref
APP/PS1	8 months	4 days - analysis 6 days later	↓	↓		↓ dendritic branches, ↓ dendritic spines, ↓synaptic markers	46
	10 months	-		↓		↓ dendritic branches, ↓synaptic markers	47
	8-9 months	7 days - analysis 18 hours later	↓			= Nestin, = Ki67/Nestin	51
	6 months	4 days (twice per day) - analysis 24 hours later	↓				52
	2, 4, 6 months	3 days - analysis 3 days later		↓ at 4 and 6 months	↓ at 6 months	↓ BLBP+ stem cells at 6 months	56
	12 months	3 days (twice per day) - analysis 2 weeks later	↓	↓		↓ Nestin, ↓ synaptic proteins	75
	12 months	7 days - analysis 1 day later	↓				78
	8 months	-				↓ Sox2	83
	2 months	EdU 7 days - analysis one month later				↓ EdU, ↓ EdU/NeuN	87
	3 months	3 days (twice per day) - analysis 5 weeks later	↓BrdU/NeuN			↓dendritic ramification ↓Spine density	109
	8 months	3 weeks - analysis at the end	↓	↓		↓BrdU/NeuN	113
	7 months	12 days - analysis 1 day (a) or 30 (b) days later	= (a), ↓ (b)		↓ (b)	= Ki67+ cells, ↓ Brdu+/NeuN+/S100b-,↓ Brdu+/DCX+/NeuN-, ↓ Brdu+/DCX-/NeuN+	127
APP/PS1ΔΕ9	28 weeks	7 days (twice per day) - analysis 7 days later	↓	↓		↓ NeuN	44
	3 months	3 days - analysis 2 hours (a) or 4 weeks (b) later	=	↓		↓ NeuN	57
	2 months	3 days (twice per day)	↓		↓		67
	3,9,18 months	1 day - analysis 18 hours later	= (all ages)	↓ at 18 months		↓ total DG cells at 18 months	72
	3 months	3 days - analysis 1 day later	↓	↓		↓ NeuN	73
	4, 10 months	2 days (a), 3 days (b) - analysis 1 day later (a), (b)	↓ at 4 and 10 months	↑ at 3 months, = at 10 months			80
	9 months	-				↓Ki67, ↓synaptic proteins	82
	8-9 months	-				↓ newborn (GFP+), ↓ spine density	85
	2 months	1 injection - analysis 1 day and 14 days later	↓ in enriched mice		↓ in enriched mice	↓ DG cells and ↓ BrdU/NeuN in enriched mice	86
	3 months	3 days - analysis 3 hours (a) and 4 weeks later (b)	↓(a), = (b)		↓(a), = (b)	= (b) BrdU/NeuN	88
	3,5,10,15months	1 injection - analysis 1 day later	↓ at 3, 5, 10 months	↓			126
	3,10,13 months	5 days - analysis 4 weeks later	↓	=	=	↑ PCNA, ↑ PCNA/DCX at 3 months, ↓BrdU/NeuN	128
	9,13 months	4 days (twice per day) - analysis at day 4	↓			↓ GFAP/Sox	129
APP/PS1/Nestin-GFP	7 days; 1, 3 7 months	1 day - analysis 2 (a) or 3(b) hours later	↓			↓ Nestin, ↑ DCX/Nestin at 3 and 7 months, ↓ Spine density at 3 and 7 months	84
PS1M146L	2 months	1 injection - analysis 1 day and 14 days later	↓ in enriched mice		↓ in enriched mice	↓ BrdU/Tub and BrdU/NeuN in enriched mice	86
PS1/PS2-KO	7-9, 18-20 months	1 injection - analysis 1 day later	↑	↑		↑Brdu/NeuN, ↑ BrdU/GFAP	130
APP/PS1 KI	2, 6 months	-		↓ at 6 months			71
	6 months	-		↓			79
aAPP751	1,3,6,9 months	1 day before grafting - analysis 1,3,6,9 months later	↓	↓		↓ Synaptic markers	55
APPSw,Ind	4 months (plus 7 weeks EE)	5 days- analysis 7 weeks later	↓	↓		↓BrdU/NeuN, ↓ dendritic ramification, ↓ DG volume	50
Tg2576	3,6, 9 months	3 days - analysis 1 day later	↓				43
	3,5 months	-		=		↑ PCNA, ↑ PCNA/DCX at 3 months	128
	3, 5, 12, months	1 day - analysis 1 day (a) or 30 days (b) later	↓ at 3 months			↓ Brdu/NeuN, ↓ dendritic ramification, ↓ spine density at 3 months	131
						BrdU+/DCX+/NeuN+ at 3 months, Brdu+/DCX-/NeuN- at 12 months
Tg19959	5 weeks; 10, 15 months	-		↑ at 5 weeks		↑ Ki67	132
Arg-61	3-12 months	-		↑ at 3 months, ↓ at 12 months			133
3xTgAD	3 months	1 day - analysis 1 day later	↓				48
PDAPP	2, 12 months	1 injection - analysis 2 hours (a) and 4 weeks (b) later	↓(a) and (b)	↓(a)		= Brdu/NeuN and =BrdU/GFAP (b)	134
PDGF-APP	3,12 months	3 days - analysis 7 days later	↑	↑			34
CRND8	3, 7 months	3 days - analysis 1 day (a) and 5 weeks (b) later	↓(a) and (b)	↓(a)		↓BrdU/NeuN (b)	74
	6, 7, 9, 11, 13 weeks	5 days - analysis 1 (a), 2 (b), 4 (c), 6 (d), 8 (e) weeks later	↑			= BrdU/NeuN at 1 and 8 weeks; ↓ Brdu/GFAP (a), = (e)	135
ApoE3, ApoE4	10 weeks	3 days (twice per day) - analysis 4 weeks later	=			= BrdU/Prox1, = Ki67/GFP/Nestin , ↓ dendritic ramification and ↓ spine density in ApoE4 vs ApoE3	62
ApoE3, ApoE4	6-7 months	1 day - analysis 1 day (a), 3 days (b), 4 weeks (c) and 10 weeks (d) later	↑ ApoE4 (a,c)		↑ ApoE4 (c)	↓ Brdu/Neun (c,d), ↑ ki67 (a), ↓ dendritic branching and ↓ GAD67 in ApoE4	63
ApoE2, ApoE3, ApoE4	10-12 weeks; 1 year	3 days - analysis 1 day later	↓ ApoE4, ↑ ApoE2/3, age- and sex-dependent				64
ApoE4	9-15 months	-	=				136
ApoE ko	10 weeks	3 days (twice per day) - analysis 4 weeks later	=			= BrdU/Prox1, ↓Ki67/GFP/Nestin, ↓ dendritic ramification , ↓ spine density	62
	6-7 months	1 day - analysis 1 day (a), 3 days (b), 4 weeks (c) and 10 weeks (d) later	↓ (b)		↓(c,d)	↓ Brdu/Neun (c,d) , ↑ BrdU/S100b (b,c,d)	63
	9-15 months	-		↑ in female, = in male			136

Table summarizes the studies investigating neurogenesis in distinct AD mouse models (column 1) at different age points (column 2). Column 3 reports details of BrdU treatment (days/number of injections and time between last BrdU injection and animal sacrifice). Columns 4, 5, and 6 refer, respectively, to quantifications of BrdU⁺, DCX⁺, and BrdU⁺/DCX⁺ cells in the dentate gyrus (DG) region. Column 7 refers to other neurogenic/synaptic markers found in the DG. Symbols indicate increase (↑), decrease (↓) or no variation (=) of specific markers as compared to wild type controls. Details including different time points (a, b) between BrdU and sacrifice of the animal are reported where necessary. Unless otherwise indicated, male mice were used in the studies. BrdU: bromodeoxyuridine; DCX: doublecortin; Ki67: proliferative marker; BLBP: brain lipid-binding protein; Nestin: nestin protein; Sox2: SRY- (sex determining region Y-) box; EdU: ethynyldeoxyuridine (BrdU analogue); S100B = S100 calcium-binding protein B; PCNA: proliferating cell nuclear antigen; GFAP: glial fibrillary acidic protein; Tub: tubuline; GAD67: glutamic acid decarboxylase 67 (GABA-synthesizing enzyme).