CD2AP at the junction of nephropathy and Alzheimer's disease

Abstract

Polymorphisms in the gene encoding CD2-associated protein (CD2AP) are associated with an increased risk for developing Alzheimer's disease (AD). Intriguingly, variants in the gene also cause a pattern of kidney injury termed focal segmental glomerulosclerosis. Recent studies have investigated the cell types and mechanisms by which CD2AP gene dosage contributes to the key pathological features of AD. This review summarizes the fundamental roles of CD2AP in mammalian cells and systems, discusses the novel pathogenic mechanisms focused on CD2AP in AD and highlights the necessity of incorporating biological sex in CD2AP research. Finally, the article draws important parallels between kidney and brain physiology based on vascular and molecular organization, links kidney disease to AD, and suggests the existence of a kidney-brain axis in AD centered on CD2AP.

Keywords: Alzheimer; Aβ; Brain-body interactions; CD2AP; Cerebrovascular function; Cognition; Kidney-brain axis; Neurodegeneration; Sexual dimorphism; Tau.

Fig. 1

Basic cellular functions of CD2AP. CD2AP plays multiple roles in the cell: 1) the adaptor regulates receptor endocytosis, signaling and degradation via ubiquitin ligases; 2) promotes trafficking of cargoes such as TrkA receptor via Rab GTPases; 3) maintains cell–cell interactions through cell adhesion and tight junction molecules, 4) modulates protein processing and cleavage, as observed for APP, 5) contributes to caveolae formation and 6) triggers cell migration via rearrangement of actin fibers. Some of the CD2AP functions are interdependent such as cell adhesion and cell migration. Most of the functions mediated by the protein involve remodeling of the actin cytoskeleton. Variations and specifics for these mechanisms can be found in the main text

Fig. 2

Cell type-specific roles of CD2AP in the pathogenesis of Alzheimer’s disease. Loss of CD2AP function in specific cell types produce features of AD at the molecular, cellular, behavioral and organismal levels. Neuronal CD2AP segregates APP from BACE1, thereby preventing the accumulation of Aβ; it also promotes APP degradation in lysosomes. Enhancing the interaction between APP and CD2AP by lactylation of the former favors the endosomal-lysosomal degradation pathway of APP and overall, reduces the burden of Aβ produced in neurons (left panel). Loss of neuronal CD2AP affects these processes, thereby resulting in the accumulation of Aβ in mouse model of amyloidosis, with implication for fibrils and plaques formation (right panel). Absence of neuronal CD2AP also promotes the hyperphosphorylation of tau by p38 kinase causing microtubule destabilization and synaptic defects. CD2AP forms neuronal inclusions similar to neurofibrillary tangles and neuropil thread‐like deposits in post-mortem AD samples where it co-localizes with hyperphosphorylated tau (right panel). The trafficking and recycling of the neurotrophic/neuroprotective TrkA receptor may be also impaired upon loss of CD2AP, contributing to loss of cholinergic neurons. Tau propagation may also be impacted by the genetic variants of CD2AP in neurons. Conversely, microglial CD2AP appears to favor the progression of homeostatic to disease-associated microglia (DAM) (right panel). Low levels of microglial CD2AP appear to restrain these cells in their homeostatic state by preventing the marking of synapses with C1q complement (to be phagocytosed) and attenuates synaptic defects in the 5XFAD mouse model. Whether mouse and human microglia mediate similar function with populations varying over disease course remain to be determined. Finally, endothelial CD2AP regulates brain vascular function in a sex-dependent manner by balancing the vasoconstriction and vasodilation through ET1/ETA ligand/receptor complex and Reelin/ApoER2 signaling, respectively. In AD, this balance is perturbed with a predominance for the vasoconstrictive effects and such alteration is tightened to loss of brain endothelial CD2AP. Loss of brain endothelial CD2AP triggers memory deficits in mice

Fig. 3

Physico-mechanical properties of immortalized human brain endothelial cells (hCMEC/D3) depleted of CD2-AP determined by atomic force microscopy (A) Schematic of the AFM setup used to measure cell stiffness via shallow indentation with a microsphere-tipped cantilever. The system detects deflection to estimate mechanical properties of subcellular regions, including the actin cortex, nucleus, and focal adhesions. B Optical image of an hCMEC/D3 cell under the AFM cantilever (left), with corresponding stiffness maps (right) showing local Young’s modulus values in the peripheral region (green arrow) and over the nucleus (yellow arrow). Stiffness values ranged from 1.19–2.36 kPa peripherally and 1.28–4.59 kPa above the nucleus. C Representative force-indentation curve with the red line indicating the fitted Hertz/Sneddon model used to calculate Young’s modulus from the approach curve; the green line shows the raw indentation curve, and the blue line corresponds to the retraction curve. Maximum indentation was limited to 500 nm to minimize cytoplasmic contributions. D Distribution of Young’s modulus values in control hCMEC/D3 cells: (i) Histogram showing frequency distribution across all sampled points; (ii) Bar graph comparing stiffness between peripheral regions and regions above the nucleus (p < 0.05, two-tailed unpaired t-test). E Distribution of Young’s modulus in CD2AP-depleted hCMEC/D3 cells: (i) Histogram shows a leftward shift in stiffness values compared to controls; (ii) Bar graph demonstrates significant stiffness reduction both peripherally and over the nucleus (p < 0.05, two-tailed unpaired t-test). F Box-and-whisker plot comparing overall cortical stiffness in control versus CD2AP-depleted cells. CD2AP knockdown significantly reduced Young’s modulus across both regions (p < 0.05, two-tailed unpaired t-test).

Fig. 4

A putative kidney-brain axis centered on CD2AP. Similarities between the kidney and the brain at the level of cellular, structural and functional organization: 1) slit diaphragm vs blood–brain barrier; 2) podocytes vs neurons with overlapping molecular composition (dynamin, synaptojanin, endophilin and 3) glomerular endothelium vs brain endothelium. In both organs, CD2AP plays key roles in a cell-type specific manner. Genetic variants in CD2AP gene cause kidney injury termed focal segmental glomerulosclerosis or AD, and patients with CKD develop memory impairment. Podocytes effacement can be related to loss of and/or dysfunctional synapses. The enrichment of CD2AP in cerebral and glomerular endothelia may be the reason why both organs are vulnerable to CD2AP genetic variants: if weakened, endothelia of both organs may be further damaged by high-volume of blood flow through the cardiac cycle. Other risk factors include diabetic conditions and ApoE genotype that has been linked to CD2AP polymorphism, brain vascular and renal functions. While brain CD2AP is important for Aβ production and potentially clearance, the kidney has the ability to clear circulating Aβ but the organ may fail in doing so in disease conditions. Indeed CKD patients display elevated levels of serum Aβ, enhanced deposition of Aβ in the brain and lower Aβ CSF levels. Taken together, a bidirectional kidney <—> brain axis centered on CD2AP may exist and be altered in AD