Madepalli Lakshmana

Background Periodontitis is a chronic inflammatory disease defined by the pathologic loss of the periodontal ligament and alveolar bone in relation to aging. Although clinical cohort studies reported that periodontitis is significantly elevated in males compared to females, emerging evidence indicates that females with dementia are at a greater risk for periodontitis and decreased alveolar bone. Objective This study aimed to evaluate whether dementia is a potential sex‐dependent risk factor for periodontal bone loss using an experimental model of periodontitis induced in the triple transgenic (3x‐Tg) dementia‐like mice and clinical samples collected from senior 65 plus age patients with diagnosed dementia. Materials and Methods We induced periodontitis in dementia‐like triple‐transgenic (3x‐Tg) male and female mice and age‐matched wild‐type (WT) control mice by ligature placement. Then, alveolar bone loss and osteoclast activity were evaluated using micro‐CT and in situ imaging assays. In addition, we performed dental examinations on patients with diagnosed dementia. Finally, dementia‐associated Aβ42 and p‐Tau (T181) and osteoclastogenic receptor activator of nuclear factor kappa‐Β ligand (RANKL) in gingival crevicular fluid (GCF) collected from mice and clinical samples were measured by enzyme‐linked immunosorbent assay (ELISA). Results Alveolar bone loss and in situ osteoclast activity were significantly elevated in periodontal lesions of 3x‐Tg females but not males, compared to wild‐type control mice. In addition, we also observed that the probing pocket depth (PPD) was also significantly elevated in female patients with dementia. Using ELISA assay, we observed that females had elevated levels of osteoclastogenic RANKL and dementia‐associated Aβ42 and p‐Tau (T181) in the GCF collected from experimental periodontitis lesions and clinical samples. Conclusion Altogether, we demonstrate that females with dementia have an increased risk for periodontal bone loss compared to males.

One of the pathological hallmarks of Alzheimer's disease (AD) is the presence of extracellular deposits of amyloid beta (Aβ) peptide. In addition to Aβ as the core component of the amyloid plaque, the amyloid precursor protein (APP) processing fragment Aβ was also found accumulated around the plaque. The APPη pathway, mainly mediated by membrane‐type 5 matrix metalloproteinase (MT5‐MMP), represents an important factor in AD pathogenesis. The proamyloidogenic features of MT5‐MMP could result from interactions with APP when trafficking between organelles, so determination of the location within the cell of APPη cleavage and interacting proteins of MT5‐MMP affecting this process will be of priority in understanding the role of MT5‐MMP in AD. In the present study, MT5‐MMP was found to be located in the nucleus, cytosol, and cytosolic subcellular granules of CHO cells that stably expressed wild‐type human APP751. MT5‐MMP fusion proteins were constructed that could localize enzyme production in the Golgi apparatus, endosome, ER, mitochondria, or plasma membrane. The fusion proteins significantly increased sAPPη when directed to the endosome, Golgi apparatus, plasma membrane, or mitochondria. Since the C ‐terminal region of MT5‐MMP is responsible for its intracellular location and trafficking, this domain was used as the bait in a yeast two‐hybrid screen to identify MT5‐MMP protein partners in a human brain cDNA library. Identified binding partners included N4BP2L1, TMX3, EIG121, bridging Integrator 1 (BIN1), RUFY4, HTRA1, and TMEM199. The binding of N4BP2L1, EIG121, BIN1, or TMX3 to MT5‐MMP resulted in the most significant increase in sAPPη production. Thus, the action of MT5‐MMP on APP occurs in multiple locations within the cell and is facilitated by site‐specific binding partners.