Abstract

Background Late-onset Alzheimer’s disease (LOAD) accounts for more than 95% of AD cases. Previously, we have described that 6% of AD patients present CAG intermediate alleles in the huntingtin gene (HTT IAs). The caudate nucleus, the most affected region in Huntington’s disease, is highly sensitive to these HTT CAG expansions, as they can induce epigenetic changes, including altered microRNA profiles. All this implies a potential source of gene expression deregulation, affecting disease onset and/or progression in LOAD patients with HTT IAs.

Methods We genotyped HTT CAG repeats and Apolipoprotein E (APOE) in postmortem brain frozen samples from 323 LOAD patients and 335 healthy controls. From them, we selected caudate samples of HTT IA carrier and non-carrier LOAD patients and controls, with neuropathological study, and performed next-generation microRNA sequencing, in silico target prediction and pathway analysis, followed by molecular and histopathological studies.

Results Our study revealed that the presence of HTT IAs decreases survival in LOAD patients after disease onset. MicroRNA profiles in the caudate nucleus are altered in all LOAD compared to the control cases but are more pronounced in HTT IAs carriers. In silico analysis suggests that the microRNAs expressed differentially in HTT IAs carriers regulate key components of the spliceosome, affecting splicing factors of the SRSF family or the nuclear FUS-SFPQ complex, which was confirmed by different techniques. This leads to an increase in Tau 3R protein, conducting to a higher presence of ghost tangles, the last state of neurofibrillary tangles, in LOAD patients with HTT IAs. In addition, they also present a higher number of HTT-positive neurons in a CAG repeat expansion-dependent manner.

Conclusions Our findings demonstrate a synergistic effect of HTT IAs and miRNAs deregulation in the evolution of tau pathology, which could be related to an accelerated misprocessing and subsequent aggregation of the Tau 3R isoform, favoring a subsequent faster disease progression. The incorporation of genetic screening for HTT alleles into clinical practice would allow a more accurate classification of LOAD patients, facilitating the design of personalized therapeutic interventions and improving the prospects for the management of this debilitating disease.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study has been funded by Instituto de Salud Carlos III (ISCIII) through the project P21/00467 and co-funded by the European Union.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All procedures have been approved by the Ethics Committee of the Principality of Asturias (CEImPA n 2022.266).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Data Availability

All data produced in the present study are available upon reasonable request to the authors. The databases obtained and used during the current study are available on ZENODO, with the accession number “11185109” (https://doi.org/10.5281/zenodo.11185109).

AbbreviationsADAlzheimer’s diseaseAPOEApolipoprotein EE10exon 10 of MAPT geneFTDfrontotemporal dementiaFUSfused in sarcoma proteinHDHuntington’s diseaseHTT IASintermediate alleles in HTT geneHTThuntingtin proteinKEEGKyoto Encyclopedia of Genes and GenomesLOADLate-onset Alzheimer’s diseaseMAPTmicrotubule associated Tau genemHTTmutant huntingtinmiRNAsmicroRNAsNDsneurodegenerative diseasesNFTsneurofibrillary tanglesPCAprincipal component analysisPLAproximity ligation assayPMIpostmortem intervalpolyQenlarged polyglutamine tractRBPRNA binding proteinRINRNA integrity numberRPMread per millionRTroom temperatureSFPQProline/Glutamine rich splicing factorSRSFSerine/Arginine rich splicing factor