Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer’s brains

Abstract

PICALM, a clathrin adaptor protein, plays important roles in clathrin-mediated endocytosis in all cell types. Recently, genome-wide association studies identified single nucleotide polymorphisms in PICALM gene as genetic risk factors for late-onset Alzheimer disease (LOAD). We analysed by western blotting with several anti-PICALM antibodies the pattern of expression of PICALM in human brain extracts. We found that PICALM was abnormally cleaved in AD samples and that the level of the uncleaved 65-75 kDa full-length PICALM species was significantly decreased in AD brains. Cleavage of human PICALM after activation of endogenous calpain or caspase was demonstrated in vitro. Immunohistochemistry revealed that PICALM was associated in situ with neurofibrillary tangles, co-localising with conformationally abnormal and hyperphosphorylated tau in LOAD, familial AD and Down syndrome cases. PHF-tau proteins co-immunoprecipitated with PICALM. PICALM was highly expressed in microglia in LOAD. These observations suggest that PICALM is associated with the development of AD tau pathology. PICALM cleavage could contribute to endocytic dysfunction in AD.

The Role of PICALM in Alzheimer’s Disease

“…Further, a recent study employing Western blotting analysis indicated the association between PICALM and NFTs pathology in individuals with LOAD, EOAD, and DS [90]. Also, it was found that PHF tau proteins coimmunoprecipitated with PICALM [90]. All these results are suggestive of the involvement of PICALM in tauopathy of AD.…”

“…However, it was suggested that CSF profile combining Aβ1-42 and p-tau181 was linked to rs541458 (OR=0.68, 95 % CI=0.47-0.98) rather than rs3851179 [99]. Further, a recent study employing Western blotting analysis indicated the association between PICALM and NFTs pathology in individuals with LOAD, EOAD, and DS [90]. Also, it was found that PHF tau proteins coimmunoprecipitated with PICALM [90].…”

“…Furthermore, Ando et al detected neither PICALM immune reactivity relevant to the Aβ deposition in the core of SP nor Aβ immune reactivity in PICALM immunoprecipitates in a postmortem examination of human LOAD brain sample, suggesting that PICALM may not directly impart influence on aggregated or oligomeric Aβ peptide [90]. On the other hand, one possible explanation of the contradictory conclusions about the role of PICALM in Aβ toxicity is that there is another process in which PICALM facilitates the inhibition of Aβ toxicity or generation.…”

“…However, it seems that PICALM can simultaneously promote production [25,88,89] and elimination [93,94] of Aβ peptide (or its neurotoxicity) via APP internalization and transportation with however subsequently disparate processing (enzymolysis in endosomes and degradation in lysosomes). Still, we may target PICALM as a potential modulator of tauopathy in the pursuit of therapeutic strategies for AD [90].…”

Caspases rule the intracellular trafficking cartel

“…The unstructured C terminus of CALM, which contains a binding domain for the AP2 complex and CHC, is cleaved at an unknown site into a 50-kDa fragment to a limited extent in SH-SY5Y neuroblastoma cells and in vitro by caspase-3 [79,80]. Proteolysis separates the C-terminal clathrin-binding domain from the ANTH (AP180 N-terminal homolog) domain in N terminus, which contains a membrane localization sequence and v-SNARE-binding region, resulting in the inhibition of CALM's function at CCPs.…”