Table 3.

NDA rodent model studies (axon-related phenotypes are highlighted in bold)

Disease	Model		Hallmarks along disease progression
AD	APP/PS1 (familiar APP and presenilin-1 mutaton)	Phenotypes	3 M: MCT 1, 2, 4↓ LDH-A↓ LDH-B↓↓ [82] OXPHO proteome change [83]	6 M: Carbohydrate metabolism↓ [84] Detectable axonal pathology [85]	10 M: Glucose flux into TCA cycle↓ [86] Widespread axonal spheroids [85, 87]
		Intervention	6 M-9 M: 15d-PGJ2 (PPARγ agonist) treatment → Glucose uptake↑ GLUT4↑ Spatial memory ↑ [88]
			7 M-8 M: Albiflorin treatment → Mito dynamics↑ Antioxidant activity↑ Spatial memory↑ [89]
			9 M-10 M: Electroacupuncture → Glucose uptake↑ GLUT1, 3↑ AMPK↑ Cognition↑ [90]
			9 M-23 M: CP2 (mito complex I mild inhibitor) → AMPK↑Glucose uptake↑ Oxidative stress↓ Cognition↑ [91]
	3xTg (familiar APP, PS1 and tau mutation)	Phenotypes	P11-19: Glycolysis↑ [92] Pentose phosphate pathway↓ [92] 1 M: Mito biogenesis↓ [93]	2 M: Regional glucose uptake↓ [94] Dystrophic axon [95] 3 M: PDH-E1α↓ Lipid peroxidation↑ [96] Axonal transport↓ [97]	6 M, 9 M: COX IV↓Oxidative stress↑ [96] 12 M: Mito respiration↓ [96] 18 M: Whole brain glucose uptake↓ [94]
		Intervention	3.5 M-18 M: CP2 (mito complex I mild inhibitor) → Glucose homeostasis↑ Cognition↑ [98]
			6 M: Intermittent hypoxic conditioning for 2wks → 8.5 M: Mitochondrial bioenergetic↑ Learning and spatial memory↑ [99]
	5XFAD (3 familiar APP and 2 familiar PS1 mutation)	Phenotypes	2 M: TCA cycle activity↓ [100] Synaptosomal glycolysis and OXPHO↓ [100] Detectable axonopathy [64] 3 M: Axonal lysosome accumulation [101]	4 M:Antioxidant proteins↓ [102] Synaptosomal mito bioenergetics↓ [103] Synaptic ATP synthase subunit ↓ [104] 5 M: Peri-axonal Abeta thread [105] BACE1 accumulates in dystrophic axon [106]	7 M: Glucose metabolism↓ (Female > Male) [107, 108] 8 M: Neurotransmitter & glutamine↓ [109]
		Intervention	OSCP overexpression → 4-5 M Mitochondrial function↑ Axonal mito dynamics and motility↑ Spatial learning and memory↑ [110]
			2 M-4 M: Ergothioneine (antioxidant) treatment → Oxidative stress↓ Glucose metabolism↑ Fear memory↑ [111]
			4 M-6 M: cx-DHED treatment → GLUT1,3↑ GLUT2↓ O-GlcNac level↑ Cognition↑ [112]
			4 M-6 M: Liraglutide (GLP-1 analog) treatment → Glycolytic support from astrocyte↑ Spatial learning and memory↑ [113]
PD	A53T α-Synuclein induction in vivo	Phenotypes	4wks post induction: Synaptic mito bioenergetics↓ [114] Altered distribution of glucose metabolism [115] 3-4wks post induction: Dystrophic axon [116, 117]	6wks post induction: Mito inclusion and fragmentation [118]	12wks post induction: Perturbed TCA cyle and amino acid metabolism [119]
		Intervention	Mdivi-1 (Drp1 inhibitor) treatment prior to induction → 8wks after: Synaptosomal mito bioenergetics↑ Motor function↑ [120]
	A53T α-Synuclein induction in vivo	Phenotypes	α-Syn oligomerized at mito membrane → OXPHO complex I activity↓ROS↑mPTP opening [121] Parkin mediated mitophagy in axon↑ → Mito loss & Bioenergetic deficit [122] (Upon oxidative stress) Gene expression of OXPHO units↓Cholesterol synthesis↓Glycolysis↑Motor proteins↓ [123]
			Axon swelling Gene expression for axon guidance & synaptogenesis↓ [124] Axon outgrowth↓ Axonal transport of vesicular cargos↓Autophagic flux↑ [125]
	LRRK2 R1441G knockin in vivo	Phenotypes	3 M: Striatal synaptosomal OXPHO units↓ [126] 2-4 M: Axonopathy in SN [127]	12 M: SN mito size↓ Mito fission↑ Autophagosome accumulation [128]	18 M: Mito ATP production↓ [129] 24 M: Ubiquitinated mito↑ [129]
	LRRK2 G2019S mutation in vitro	Phenotypes	LRRK2 interaction with Drp1↑ → Drp1 recruitment to mito → Mito fragmentation & dysfunction [130] Mito DNA damage↑ [131] NAD+↓Sirtuin activity↓Mito motility↑ Mito respiration↓Mito density in distal neurite↓ [132] Axonal transport of autophagosome↓ [133]
HD	R6/2 (Exon1 of human HD gene with 150 CAG repeats)	Phenotypes	1 M: Lactate↓ [134] 1.5 M: Glucose uptake↓ [135]	2 M: Axonal pathology in corpus callosum [136] 2.5 M: Oxidation of key metabolic enzymes [137] Axon degeneration in sciatic nerve [138]	2-3 M: Mito DNA damage↑ [139] 3 M: Mito cristae integrity↓ [140]
		Intervention	P21-3 M: bezafibrate ( pan-PPAR agonist) treatment → Mito density↑ Oxidative stress↓ Motor function↑ [141]
ALS	SOD1 G93A	Phenotypes	P15: Axonal and NMJ mito length↓ [142]	P40: Spinal cord mito respiration↓ [143] P45: Axonal mito retrograde transport↓ [142]	3 M: AMPK activation [143] Mito clustering in sciatic nerve [142] Ventral root axon loss [144]

Abbreviations: AMPK AMP-activated protein kinase, BACE1 beta-secretase 1, COX IV Cytochrome c oxidase subunit 4, cx-DHED carboxy-dehydroevodiamine·HCl, Drp1 Dynamin-related protein 1, GLP-1 Glucagon-like peptide 1, GLUT glucose transporter, LDH lactate dehydrogenase, LRRK2 Leucine-rich repeat kinase 2, M month, MCT monocarboxylic acid transporter, Mito mitochondria/mitochondrial, mPTP mitochondrial permeability transition pore, NMJ Neuromuscular junction, OSCP ATP synthase peripheral stalk subunit OSCP (ATP5PO)