Immune Targets and Passive Immunotherapy of Alzheimer's Disease

Alzheimer's disease (AD) is characterized primarily by progressive cognitive decline, which includes memory impairment, aphasia, apraxia, agnosia, damage to visual-spatial abilities, impairment of abstract thinking and calculation, as well as changes in personality and behavior. The current pharmacological approaches for these symptoms are cholinesterase inhibitors, N-methyl-D-aspartate receptor (NMDA) antagonists, and drugs targeting the brain-gut axis. However, these drugs often only alleviate symptoms rather than halt disease progression, often resulting in limited efficacy and potential side effects. There is considerable interest in improving treatment methods, with immunotherapy showing significant potential. This approach is broadly categorized into passive immunotherapy, which utilizes antibodies, and active immunotherapy, involving vaccines. Among them, passive immunotherapy is more appropriate and effective in older patients with reduced vaccine responsiveness. Moreover, when adverse reactions occur, the action of humanized monoclonal antibodies (mAbs) can be more easily stopped than that of vaccines due to their targeting of specific protein conformations. Currently, the development of passive immunotherapy for AD mainly focuses on targeting Amyloid β-protein (Aβ), tau protein, and neuroinflammation.

Passive Immunotherapy Targeting Aβ

Based on the amyloid cascade hypothesis, Aβ is considered to play a key role in the pathogenesis of AD. Amyloid precursor protein (APP) is a type I transmembrane protein predominantly found in neuronal synapses. It undergoes cleavage by β- and γ-secretase, resulting in the production of Aβ peptides. These peptides spontaneously aggregate into oligomers and protofibrils, which have been shown to exhibit significant neurotoxicity. Meanwhile, oligomers can activate neuroglial cells to trigger neuroinflammation and accelerate the development of tau pathology, thus further exacerbating the progression of AD. Therefore, strategies targeting Aβ can effectively inhibit the progression of AD.

Fig.1 Processing of APP to produce Aβ peptides.^{1, 4}

For a long time, Aβ has been the main focus of developing passive immunotherapy for AD. The mAbs against Aβ have demonstrated the effect of passive immunotherapy for AD in PDAPP mouse models for the first time. Subsequently, various anti-Aβ antibodies have been developed and used in clinical research. mAbs targeting different forms of Aβ may have different effects on Aβ aggregation and plaque clearance. For example, solanezumab mainly targets monomers, oligomers, or protofibrils of Aβ, resulting in poor efficacy of these mAbs in removing amyloid and improving cognition. In contrast, mAb such as gantenerumab preferentially binds to the protofibril form of Aβ. Donanemab mainly recognizes plaque-specific AβpE3 and is the mAb with the best therapeutic effect on plaque removal and cognition to date. Therefore, the binding affinity of mAbs to different Aβ species may play a decisive role in clinical efficacy.

Fig.2 Epitopes of Aβ recognized by the mAbs tested in clinical trials.^{2, 4}

Passive Immunotherapy Targeting Tau Protein

The second major pathological feature of AD is neurofibrillary tangles (NFTs), which are formed by the aggregation of abnormally phosphorylated Tau protein. It is speculated that phosphorylated tau plays a key role in driving tau accumulation, synaptic dysfunction, and neuronal loss. Compared with Aβ, tau protein seems to be more related to the severity of cognitive decline, so passive immunotherapy targeting tau protein is considered another attractive strategy for AD intervention.

It has been proven that anti-tau mAbs can enter neurons to target intracellular tau protein, which is mediated by membrane-mediated endocytosis. In addition, they can also inhibit the progression of AD by blocking the spread of extracellular tau. The clinical development of anti-tau mAbs is still in the early stages. So far, 11 anti-tau mAbs have entered clinical trials, targeting the N-Terminal projection and microtubule-binding domains, with main selective targets including phosphorylated tau, tau monomers, oligomers, protofibrils, insoluble tau, soluble extracellular tau, intraneuronal NFTs, etc.

Fig.3 Epitopes of tau recognized by the mAbs tested in clinical trials.^{2, 4}

Passive Immunotherapy Targeting Neuroinflammation

In the central nervous system (CNS), microglia are the major immune cells with a crucial role in neuroimmune responses and inflammation. In AD, Aβ and phosphorylated tau proteins act as damage-associated molecular patterns, recognized by receptors such as TLR-4 on microglia. Inflammatory factors are released as a result of this identification, aggravating the course of AD by encouraging the accumulation of Aβ and NFTs. Consequently, passive immunotherapy aimed at mitigating neuroinflammation presents a promising avenue for AD treatment.

• Targeting TREM2: TREM2 is a critical receptor that is selectively expressed by microglia. In AD mouse models, the absence of TREM2 increases neuronal atrophy. Agonistic antibodies targeting TREM2 can effectively activate its downstream signaling pathways to regulate microglial proliferation and immune response, thereby reducing AD pathology.
• Targeting CD38: CD38+ CD8+ T cells have been proven to be significantly increased in the blood of early AD patients and can be transported to the CNS to trigger inflammation and cytotoxicity. Targeting CD38 has immunomodulatory activity for non-plasma cells.
• Targeting CD33: CD33, a type I transmembrane protein belonging to the Ig superfamily, is an AD risk gene highly expressed in microglia. In the progression of AD, CD33 may regulate the neuroinflammatory process through its crosstalk with TREM2.
• Targeting semaphorin 4D (SEMA4D): SEMA4D is involved in the regulation of brain axon guidance. After CNS injury or in the neurons of AD patients, the expression of SEMA4D is upregulated. It activates neuroglial cells, resulting in an inflammatory cytokine release and inducing impairment of neuronal and oligodendrocyte function.
• Targeting galectin-3: In AD patients and corresponding mouse models, there is an observed increase in galectin-3 expression within microglia in association with amyloid plaques. Studies have shown that the absence of galectin-3 in 5×FAD mice reduced the amyloid plaque load and improved cognitive function.