Positive Allosteric Modulators of Trk Receptors for the Treatment of Alzheimer's Disease

Abstract

Neurotrophins are important regulators of neuronal and non-neuronal functions. As such, the neurotrophins and their receptors, the tropomyosin receptor kinase (Trk) family of receptor tyrosine kinases, has attracted intense research interest and their role in multiple diseases including Alzheimer's disease has been described. Attempts to administer neurotrophins to patients have been reported, but the clinical trials have so far have been hampered by side effects or a lack of clear efficacy. Thus, much of the focus during recent years has been on identifying small molecules acting as agonists or positive allosteric modulators (PAMs) of Trk receptors. Two examples of successful discovery and development of PAMs are the TrkA-PAM E2511 and the pan-Trk PAM ACD856. E2511 has been reported to have disease-modifying effects in preclinical models, whereas ACD856 demonstrates both a symptomatic and a disease-modifying effect in preclinical models. Both molecules have reached the stage of clinical development and were reported to be safe and well tolerated in clinical phase 1 studies, albeit with different pharmacokinetic profiles. These two emerging small molecules are interesting examples of possible novel symptomatic and disease-modifying treatments that could complement the existing anti-amyloid monoclonal antibodies for the treatment of Alzheimer's disease. This review aims to present the concept of positive allosteric modulators of the Trk receptors as a novel future treatment option for Alzheimer's disease and other neurodegenerative and cognitive disorders, and the current preclinical and clinical data supporting this new concept. Preclinical data indicate dual mechanisms, not only as cognitive enhancers, but also a tentative neurorestorative function.

Keywords: Alzheimer’s disease; brain-derived neurotrophic factor (BDNF); nerve growth factor (NGF); neurodegeneration; neurotrophins.

Figure 1

A schematic timeline showing a selection of major achievements in the identification or development of positive modulators of neurotrophin signaling including publication of scientific articles, submission of patent applications or performed clinical trials.

Figure 2

(a) A schematic representation of Trk receptor expression summarized from [21,24,25,26,27] and the Human Protein Atlas initiative (https://www.proteinatlas.org, accessed on 16 June 2024) where red indicates high levels and blue indicates low levels of expression. Figures (b,c) are RNAseq data from Allen Brain Map, Allen Institute for Brain Science; Human multiple cortical areas—SMART-seq (https://celltypes.brain-map.org/rnaseq, accessed on 16 June 2024). (b) This data set includes single-nucleus transcriptomes from 49,495 nuclei across multiple human cortical areas. Individual layers of cortex were dissected from tissues covering the middle temporal gyrus. (c) The data set includes single-cell transcriptomes from 76,533 total cells derived from two post-mortem human brain specimens in the primary motor cortex.

Figure 3

Schematic representation of Trk signaling pathways. The arrows on the upper part indicate suggested sites for interaction between small-molecule modulators and Trk receptors. Phosphotyrosine residues on TrkA are highlighted in yellow circles. Some phosphotyrosine residues are numbered according to the amino acid sequence of TrkA and their interaction with adaptor proteins SHC1, PI3K, and PLCγ are indicated. Functional outcomes are depicted in light blue boxes with citations in square brackets. The figure was created with BioRender.com (https://biorender.com, accessed on 16 June 2024).

Figure 4

Schematic view of different possible therapeutic modalities on Alzheimer’s disease progression.

Figure 5

A schematic representation of biomarkers and clinical course of AD and putative temporal treatment options for second-generation symptomatic or disease-modifying treatments.

Figure 6

Chemical structure of compounds disclosed in patent applications of scientific journals.