Table 2.

Adverse effects of lowering Aβ

Role	Experimental paradigm	Adverse effects	References
Synaptic activity LTP	APP or BACE1 knockout	Cognitive deficits induced and impaired LTP	Dawson et al. [53], Laird et al. [139], Lombardo et al. [154], Wang et al. [272, 273]
	Treatment with anti-Aβ antibody 4G8	LTP formation prevented	Morley et al. [185], Puzzo et al. [210]
	Infusion of anti-Aβ antibody 4G8 or siRNA to APP	Short-term memory abolished in contextual fear conditioning or the Morris Water Maze	Garcia-Osta and Alberini [81], Morley et al. [185], Puzzo et al. [210]
	BACE1 inhibitor treatment (wild-type mice)	Suppression of LTP, impaired cognitive performance	Filser et al. [74]
Regulation of neuronal hyperexcitability	APP or BACE1 knockout	Hypersensitivity to spontaneous and induced seizures	Hitt et al. [103], Hu et al. [112], Kobayashi et al. [130], Steinbach et al. [243]
Neurogenesis and synaptogenesis	APP knockout	↓ Neuronal branching and synapse formation	Southam et al. [239]
	APP knockout	Loss of synaptic proteins	Dawson et al. [53], Seabrook et al. [228]
	BACE1 knockout	Hearing impairment linked to aberrant synaptic organisation in the cochlea	Dierich et al. [60]
	BACE1 inhibitor treatment (wild-type mice)	↓ Spine density, ↓ spine formation	Filser et al. [74]
Myelination Regulation of myelination	BACE1 knockout	Delayed myelination, ↓ myelin thickness	Hu et al. [110], Willem et al. [280]
	BACE1 knockout	Impaired remyelination of peripheral nerves after injury	Hu et al. [109, 111]
Role in blood vessels Promotion of angiogenesis	BACE1 knockout	↓ In retinal vascular density	Cai et al. [38]
	APP-deficiency or BACE1 inhibitor treatment	Shorter hindbrain vessels, fewer cerebrovascular branches	Luna et al. [163]
	γ-secretase inhibitor treatment	↑ Angiogenesis and vascularisation	Cameron et al. [40]
“Vascular plug”	Aβ-targeting drugs (active or passive Aβ immunisation) in human clinical trials	Microhaemorrhages and brain oedema (“Amyloid-Related Imaging Abnormalities” (ARIA))	Penninkilampi et al. [203], Sperling et al. [240]
	Aβ immunisation (animal models)	ARIA-like cerebral microbleeds	Blockx et al. [24], Joseph-Mathurin et al. [121]
	APP or BACE1 knockout	↑ Mortality after ischaemic injury, deficits in reactive blood flow	Koike et al. [133]
Response to injury Promotion of recovery	BACE1 knockout	Impaired remyelination after sciatic nerve lesion	Hu et al. [109, 111]
	BACE1 knockout	Worse functional outcome after spinal cord injury	Pajoohesh-Ganji et al. [195]
	BACE1 knockout	Worse outcome after controlled cortical impact (rescued by Aβ application)	Mannix et al. [167, 168]
	BACE1 or APP knockout	↑ Risk of mortality following cerebral ischaemia	Koike et al. [133]
Antimicrobial activity	APP knockout	↑ Mortality after infection	Kumar et al. [138]
	Aβ-targeting therapies	↑ Incidence of infections	Gosztyla et al. [87]
Iron homeostasis Regulation of iron homeostasis	APP knockout	↑ Neuronal iron retention in vitro, ↑ vulnerability to oxidative damage from dietary iron in vivo	Duce et al. [63]
	APP knockout	Age-dependent iron accumulation in the brain and liver	Belaidi et al. [16]
Glucose metabolism	BACE1 knockout	↓ Insulin expression in the pancreas	Hoffmeister et al. [104]
	BACE1 knockdown (siRNA)	↓ Insulin mRNA and protein in insulinoma cells	Hoffmeister et al. [104]

Summary of studies reporting adverse outcomes after lowering Aβ in a range of experimental systems