BioMed Research International

Review Article

Derailed Intraneuronal Signalling Drives Pathogenesis in Sporadic and Familial Alzheimer’s Disease

Table 1

Sporadic and familial AD risk genes and nongenetic positive risk factors and possible pathogenic mechanisms [8, 132].


Risk factor	Possible mechanism(s)*		References**
Risk factor	A homeostasis	Cellular signaling	References**

Genetic
APP	APP processing	Erk1/2	[61]
PS1	Change in A40/A42 ratio	Wnt-signalling, Erk1/2, Akt, and Ca²⁺ signaling	[61, 64–66, 133]
PS2	APP processing	Erk1/2	[65, 134, 135]
BACE	APP processing	cAMP-PKA-CREB signaling	[68]
ApoE4	Aβ clearance	Erk1/2, JNK	[136–140]
SORLA	APP processing	Neurotrophin signaling	[137, 141, 142]
EPHA1	?	Ephrin signalling (Erk1/2)	[143, 144]
MS4A6A/MS4A4A	?	Signalling	[132]
CD2AP	?	PI3K-Akt-GSK3 (podocytes)	[145]
CLU	Aβ sequestering	Leptin/clusterin signalling; p53-Dkk1-JNK pathway	[146–148]
2-AR	?	PKA, Erk1/2, and JNK	[149, 150]
CD33	Aβ clearance		[151]
PICALM	APP processing	Regulation of receptor-mediated endocytosis?	[152]
BIN1	APP processing	Ca²⁺ dyshomeostasis	[153]
ABCA7	Aβ clearance	?	[154]

Nongenetic
Smoking	?	Erk1/2 activation by oxidative stress	[155, 156]
Obesity	?	Cytokine-induced activation of MAPKs (p38, JNK); leptin signalling	[157–160]
Traumatic brain injury (TBI)	APP processing	Activation of MAPKs (Erk1/2, p38, and JNK), Akt, GSK3	[8, 161]
Type II diabetes	?	Insulin signalling, cytokine-induced activation of MAPK’s (p38, JNK)	[158–160, 162]
Stress (hormones)	?	Glucocorticoid-induced activation of Erk1/2, JNK; oxidative stress-induced JNK-dependent APP processing	[163–166]
Anaesthetics		Activation of MAPKs (Erk1/2, JNK)	[167–170]
Ageing	APP processing	Impaired Ca²⁺ dyshomeostasis and signalling, elevated cytokine signalling (“inflammaging”), impaired mitochondrial function with altered redox signalling (MAPKs, PI3K/Akt)	[171–174]

*Not exhaustive. **Including reviews with original research papers cited.