Journal Article

Dendritic location of dystrophic neurites in FTLD‐TDP type C with annexinopathy

Keszycki, Rachel, Macomber, Alyssa, Gefen, Tamar, Zouridakis, Antonia, Jamshidi, Pouya, Geula, Changiz, Nelson, Caroline, Kawles, Allegra, Minogue, Grace, Mesulam, M‐Marsel, Castellani, Rudolph J.

2026

Overview

The type C variant (TDP‐C) of FTLD‐TDP exhibits unique features, not shared by types A and B, namely the invariable and frequently asymmetric predilection for the anterior temporal lobes (ATL). Depending on the direction of hemispheric asymmetry, the associated clinical features include word comprehension impairment, associative agnosia, and behavioral abnormalities. Current research on TDP‐C aims to explore the factors that underlie the selective targeting of the ATL and, more specifically, the cellular details that undermine the behavioral and cognitive functions of this region. Abnormal TDP‐C neurites have recently been shown to represent heterodimers with annexin A11 (ANXA11). This feature, not shared by TDP‐A or ‐B, may explain the unique predilection of TDP‐C for the ATL. To further explore the subcellular distribution of the pathology, paraffin‐embedded sections were stained using fluorescent antibodies for the dendritic marker MAP2 and phosphorylated TDP‐43 (pTDP) or ANXA11. Results indicated that approximately half of pTDP/ANXA11 neurites co‐localized with MAP2. The actual overlap during life may be much higher but decreased at autopsy through dendritic loss due to prolonged neurodegeneration. The potentially selective and progressive dendritic pathology of TDP‐C, quite unique among neurodegenerative entities, may underlie the distinctive perturbation of cortical integrative computations. The type C variant of FTLD‐TDP (TDP‐C) is defined by long dystrophic neurites that are immunopositive for both phosphorylated TDP and annexin A11 (ANXA11). Kawles et al. are the first paper to systematically show that these neurites are likely of dendritic origin.

• Publisher: John Wiley & Sons, Inc
• Subject: Abnormalities / Aged / Aged, 80 and over / Annexins - metabolism / Asymmetry / Autopsies / Autopsy / Axons / Cognitive ability / Dendrites - metabolism / Dendrites - pathology / Dendritic structure / DNA-Binding Proteins - metabolism / dystrophic neurites / Female / Fluorescence / Frontotemporal Lobar Degeneration - metabolism / Frontotemporal Lobar Degeneration - pathology / FTLD‐TDP / FTLD‐TDP‐C / Hemispheric laterality / Humans / Male / Middle Aged / Neurites - metabolism / Neurites - pathology / Neurodegeneration / Pathology / TDP type C / TDP‐43 / Temporal Lobe - metabolism / Temporal Lobe - pathology