Alzheimer’s disease (AD) and targets

1, Tau/MAPT(P10636 ) and Amyloid-β (Aβ) peptide/Aβ1-42(P05067)

The microtubule-associated protein tau and amyloid-β (Aβ) are key players in Alzheimer’s disease (AD). Aβ and tau are linked in a molecular pathway at the post-synapse with tau-dependent synaptic dysfunction being a major pathomechanism in AD.
Alzheimer disease (AD) is the most common form of dementia. Pathologically, AD is characterized by amyloid plaques and neurofibrillary tangles in the brain, with associated loss of synapses and neurons, resulting in cognitive deficits and eventually dementia. Amyloid-β (Aβ) peptide and tau protein are the primary components of the plaques and tangles, respectively. In the decades since Aβ and tau were identified, development of therapies for AD has primarily focused on Aβ, but tau has received more attention in recent years, in part because of the failure of various Aβ-targeting treatments in clinical trials. 
Tau is the major microtubule associated protein (MAP) of a mature neuron. The other two neuronal MAPs are MAP1 and MAP2. An established function of MAPs is their interaction with tubulin and promotion of its assembly into microtubules and stabilization of the microtubule network. The microtubule assembly promoting activity of tau, a phosphoprotein, is regulated by its degree of phosphorylation. 

2, APOE,APOE4   (P02649)
Alzheimer's disease (AD) is one of the most devastating neurodegenerative diseases. It has been known for decades that the APOE ɛ4 allele is the most significant genetic risk factor for late-onset AD and yet its precise role in the disease remains unclear. The APOE gene encodes apolipoprotein E (apoE), a 35 kDa glycoprotein highly expressed in the brain. Apolipoprotein E (APOE) is the major cholesterol carrier in the brain, affecting various normal cellular processes including neuronal growth, repair and remodeling of membranes, synaptogenesis, clearance and degradation of amyloid β (Aβ) and neuroinflammation. In humans, the APOE gene has three common allelic variants, termed E2, E3, and E4. APOE4 is considered the strongest genetic risk factor for Alzheimer’s disease (AD), whereas APOE2 is neuroprotective. 

3, CD33(P20138)  TREM2(Q9NZC2)

The microglial receptors CD33 and TREM2 have been associated with risk for Alzheimer's disease (AD). Here, we investigated crosstalk between CD33 and TREM2. We showed that knockout of CD33 attenuated amyloid beta (Aβ) pathology.

4, LIMK1(P53667)
Alzheimer's disease (AD) therapies predominantly focus on β-amyloid (Aβ), but Aβ effects may be maximal before clinical symptoms appear. Downstream of Aβ, dendritic spine loss correlates most strongly with cognitive decline in AD. Rho-associated kinases (ROCK1 and ROCK2) regulate the actin cytoskeleton, and ROCK1 and ROCK2 protein abundances are increased in early AD. Here, we found that the increased abundance of ROCK1 in cultured primary rat hippocampal neurons reduced dendritic spine length through a myosin-based pathway, whereas the increased abundance of ROCK2 induced spine loss through the serine and threonine kinase LIMK1. 

5, BACE1(P56817)

Reducing production of amyloid-β (Aβ) peptide by direct inhibition of the enzymes that process amyloid precursor protein (APP) is a central therapeutic strategy for treating Alzheimer's disease. However, small-molecule inhibitors of the β-secretase (BACE1) and γ-secretase APP processing enzymes have shown a lack of target selectivity and poor penetrance of the blood-brain barrier (BBB). Here, we have developed a high-affinity, phage-derived human antibody that targets BACE1 (anti-BACE1) and is anti-amyloidogenic. Anti-BACE1 reduces endogenous BACE1 activity and Aβ production in human cell lines expressing APP and in cultured primary neurons. Anti-BACE1 is highly selective and does not inhibit the related enzymes BACE2 or cathepsin D. 

6，TARDBP(Q13148)
TDP-43 inclusions are found in many Alzheimer’s disease (AD) patients presenting faster disease progression and greater brain atrophy. Previously, we showed full-length TDP-43 forms spherical oligomers and perturbs amyloid-β (Aβ) fibrillization. To elucidate the role of TDP-43 in AD, here, we examined the effect of TDP-43 in Aβ aggregation and the attributed toxicity in mouse models. We found TDP-43 inhibited Aβ fibrillization at initial and oligomeric stages. Aβ fibrillization was delayed specifically in the presence of N-terminal domain containing TDP-43 variants, while C-terminal TDP-43 was not essential for Aβ interaction.

References：

1)    Understanding the Role of ApoE Fragments in Alzheimer's Disease，PMID: 30225748
2)    ApoE Lipidation as a Therapeutic Target in Alzheimer’s Disease，PMID: 32882843
3)    APOE and Alzheimer’s Disease: Advances in Genetics, Pathophysiology, and Therapeutic Approaches，PMID: 33340485
4)    Apolipoprotein E in Alzheimer's disease: an update，PMID: 24821312
5)    Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies，PMID: 31367008
6)    Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy，PMID: 23296339
7)    Reconstruction of the human blood–brain barrier in vitro reveals apathogenic mechanism of APOE4 in pericytes, PMID: 32514169
8)    APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches，PMID: 33340485
9)    Tau-targeting therapies for Alzheimer disease, PMID: 29895964
10)    Tau in Alzheimer Disease and Related Tauopathies, PMID: 20678074
11)    Dendritic Tau in Alzheimer’s Disease, PMID: 30001506
12)    CD33 modulates TREM2: convergence of Alzheimer loci, PMID: 26414614
13)    TREM2 and Risk of Alzheimer’s Disease — Friend or Foe?, PMID: 26107057
14)    TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease, PMID: 31301936
15)    Friend, Foe or Both? Immune Activity in Alzheimer’s Disease, PMID: 31920620 
16)    Pharmacologic inhibition of LIMK1 provides dendritic spine resilience against β-amyloid，PMID: 31239325

17)    Current therapeutic targets for the treatment of Alzheimer's disease, PMID: 20420492

18)    A therapeutic antibody targeting BACE1 inhibits amyloid-β production in vivo，PMID: 21613622

19)    Inflammation and Alzheimer’s disease，PMID: 10858586
20)    The metallobiology of Alzheimer's disease，PMID: 12689772
21)    Alzheimer's disease: strategies for disease modification，PMID: 20431570
22)    Neuroinflammation in Alzheimer's disease: Current evidence and future directions；PMID: 27179961
23)    Alzheimer's Disease and Parkinson's Disease，PMID: 12672864
24)    A Century of Alzheimer's Disease，PMID: 17082447 
25)    Neuropathologic Changes in Alzheimer's Disease，PMID: 12934968 
26)    Diagnosis of Alzheimer's Disease，PMCID: PMC1668726