Activity-dependent neuroprotective protein (ADNP) exhibits striking sexual dichotomy impacting on autistic and Alzheimer’s pathologies

Abstract

Activity-dependent neuroprotective protein (ADNP) is a most frequent autism spectrum disorder (ASD)-associated gene and the only protein significantly decreasing in the serum of Alzheimer's disease (AD) patients. Is ADNP associated with ASD being more prevalent in boys and AD more prevalent in women? Our results revealed sex-related learning/memory differences in mice, reflecting hippocampal expression changes in ADNP and ADNP-controlled AD/ASD risk genes. Hippocampal ADNP transcript content was doubled in male vs female mice, with females showing equal expression to ADNP haploinsufficient (ADNP+/−) males and no significant genotype-associated reduction. Increased male ADNP expression was replicated in human postmortem hippocampal samples. The hippocampal transcript for apolipoprotein E (the major risk gene for AD) was doubled in female mice compared with males, and further doubled in the ADNP+/− females, contrasting a decrease in ADNP+/− males. Previously, overexpression of the eukaryotic translation initiation factor 4E (eIF4E) led to ASD-like phenotype in mice. Here, we identified binding sites on ADNP for eIF4E and co-immunoprecipitation. Furthermore, hippocampal eIF4E expression was specifically increased in young ADNP+/− male mice. Behaviorally, ADNP+/− male mice exhibited deficiencies in object recognition and social memory compared with ADNP+/+ mice, while ADNP+/− females were partially spared. Contrasting males, which preferred novel over familiar mice, ADNP+/+ females showed no preference to novel mice and ADNP+/− females did not prefer mice over object. ADNP expression, positioned as a master regulator of key ASD and AD risk genes, introduces a novel concept of hippocampal gene-regulated sexual dimorphism and an ADNP+/− animal model for translational psychiatry.

Maternal immune activation: Implications for neuropsychiatric disorders

“…This conundrum is not an issue for MIA alone but rather has surfaced in the field of genetics as well with increasing evidence for associations between specific genes and a similarly wide range of CNS disorders(52–54). How MIA or genetic mutations can cause such a wide range of disorders is unknown, but both may act to prime an individual for second hits and the nature and timing of those second hits may determine when and which disease will result, if any (Figure 1).…”

The Eight and a Half Year Journey of Undiagnosed AD: Gene Sequencing and Funding of Advanced Genetic Testing Has Led to Hope and New Beginnings

“…ADNP haploinsufficient mice survive but show learning and memory deficits (5), in a sex-dependent manner (6). At the protein level, we have shown multiple crucial interactions for ADNP including direct binding to the chromatin remodeling complex SWI/SNF and interaction with heterochromatin protein 1 alpha (7, 8).…”

Blood-Borne Activity-Dependent Neuroprotective Protein (ADNP) is Correlated with Premorbid Intelligence, Clinical Stage, and Alzheimer’s Disease Biomarkers

“…Employing complete gene array, the Gozes laboratory discovered that ADNP regulates >400 genes during brain development and directly interacts with the ApoE promoter region [13]. ADNP deficiency results in marked increases in ApoE expression [13], especially in the female mouse brain [14]. Furthermore, ADNP haploinsufficient mice exhibit aging-related tauopathy, neurodegeneration, and cognitive deficits [15].…”