Quercetin-loaded cellulose nanofibers improve memory, learning, and attenuate endoplasmic reticulum stress in a rat model of Alzheimer's disease.

Huntington’s disease (HD) is a fatal, monogenic neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in exon 1 of (), producing a polyglutamine-expanded huntingtin protein [, ]. Although mutant HTT (mHTT) is expressed ubiquitously from development through adulthood [, ], motor symptoms typically emerge ~ 30–50 later, preceded by a prolonged prodromal phase [–] characterized by asynchronous somatic CAG repeat expansion []. Defining the temporal sequence of molecular changes preceding cellular failure is essential for understanding selective vulnerability and identifying therapeutic targets to rescue neuronal dysfunction. Striatal degeneration is a neuropathological hallmark of HD []. A 30–40% reduction in striatal volume and functional connectivity deficits can be detected a decade before clinical diagnosis [–], reflecting early disruption of basal ganglia circuitry []. Progressive loss of spiny projection neurons (SPNs), which comprise > 90% of striatal neurons and serve as the main input of the basal ganglia motor loop, underlies striatal dysfunction []. Both direct (dSPN) and indirect (iSPN) pathway neurons are affected, with iSPNs exhibiting greater vulnerability [, ]. Preferential degeneration of striosomal SPNs early in disease indicates compartment-specific susceptibility [–], although the molecular basis for differential SPN susceptibility remains unclear. HD pathology extends beyond the basal ganglia. Neuroimaging and post-mortem studies reveal disrupted corticostriatal connectivity, white matter loss, and cortical thinning [, , –]. Up to 40–50% of cortical pyramidal neurons are lost, particularly in layers III and V-VI [, ], and cortical atrophy correlates with motor deficit severity []. Thus, early dysfunction of cortical projection neurons (CPNs) and their SPN targets implicates progressive corticostriatal disconnection in HD pathogenesis.