Table 1 | Non-HSA21 protein abnormalities..

Protein	Function; substrates	AD/AD mouse	ref
Tau	Microtubule-associated protein	Hyperphosphorylated in AD; comprises neurofibrillary tangles (NFT)	[38]
pTau-Thr212	Phosphorylated by DYRK1A, CDK5, GSK3B		[38]
Nr1, NR2A, NR2B	Subunits of the NMDAR ionotropic glutamate receptor; involved in synaptic plasticity and memory	Hyperactivated in AD. No change in Tg2576 hippocampus	[11,39]
GSK3B	Kinase; Tau	Increased pGSK3B-tyr216 in AD; co-localizes with NFT	[40]
pGSK3B-Ser9	Phosphorylation inhibits activity
pGSK3B-Tyr216	Phosphorylation activates
FYN	Tyr kinase; Tau-tyr18; same site as PP2A; complexes with Tau, NR2B, PSD95	Increased in AD; knockdown in 3xTg-AD mice increases Aβ & L/M deficits	[41-44]
pSRC-Tyr416	pNR2B-Tyr1472		[41-44]
CDK5	Ser-Thr kinase; Tau; inhibit SRC activity		[45-47]
P35/25	Activates CDK5;	Increased Aβ	[48-49]
PP2A-A	Phosphatase (regulatory subunit); Tau; same site as FYN	Expression & activity decreased in AD	[50-52]
CANA	Ca++-calmodulin dependent protein phosphatase (catalytic subunit); Tau, NR1, NR2B	Increased levels in nucleus in AD brain; inhibition rescues L/M and LTD in Tg2576	[53-55]
IL1B	Cytokine; stimulates astrocyte proliferation	Increased in AD, DS; inhibition in 3xTg-AD mice rescues L/M deficits, decreases activity of CDK5 & GSK3B, and decreases levels of pTau & S100B	[14,56]
ERBB4	Neuregulin 1 receptor; cleaved by γ-secretase; c-terminal transcription factor	Increased in AD & APP/PSEN1 AD mice; protects AD mice from APP C-terminal peptide toxicity	[57,58]
NUMB	Scaffold protein involved in endocytosis; binds γ-secretase cleaved APP & NOTCH intracellular domains; inhibits Notch signaling; 4 protein isoforms differentially regulate APP processing & trafficking	Altered isoform proportions in AD and 3xTg-AD mice increase Aβ production	[59-62]
pNUMB-Ser276	Phosphorylated by aPCK & CAMKI; inhibits function in endocytosis		[63]
nNOS	Nitric oxide synthase	Decreased activity in AD contributes to cerebral amyloid angiopathy; increased levels in APP double mutant rescue L/M	[64,65]
SNCA	Presynaptic protein; component of amyloid plaques in AD	Increased in AD; decreased in cortex of DS model Ts65Dn	[66]
CASP3	Pro-apoptotic cysteine-aspartic acid protease; cleaves & activates calcineurin; cleaves APP	Increased activity in Tg2576; activates calcineurin; inhibition rescues LTD and partially rescues L/M	[39]

Table 1: Non-HSA21 protein abnormalities in AD and AD mouse models. 3xTg-AD, triple transgenic AD model expressing mutated forms of APP, Tau and PSEN1; Tg2576, transgenic mouse expressing the Swedish APP mutation; APP/PSEN1 AD mice, double transgenic expressing APP plus PSEN1 mutations. L/M, learning/memory; LTD, long term depression.

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