Histological changes in thalamus in short term survivors following traumatic brain injury: An autopsy study
NEUROLOGY INDIA
Authors: Bisht, Ajay; Garg, Kanwaljeet; Agarwal, Deepak; Singh, Pankaj Kumar; Satyarthee, Guru Dutt; Gupta, Deepak; Sinha, Sumit; Kakkar, Aanchal; Suri, Vaishali; Lalwani, Sanjeev; Kale, Shashank Sarad; Sharma, Bhawani Shankar
Abstract
Background: Severe traumatic brain injury (TBI) is a major cause of morbidity and mortality. Reduction of thalamic volumes were seen in upto 80% of patients who survived for more than 3 months after TBI. However, the same may not be true in patients who died earlier following TBI. Aims: To to study the thalamus for evidence of any injury in short term survivors of TBI (<5 days) using immunohistochemistry to look for evidence of acute thalamic injury. Materials and Methods: A cross sectional prospective study was done in which autopsy specimens of short term survivors of TBI (<5 days) were studied for histopathological changes. Results: A total of 16 patients with a mean age of 37.8 years were included in the study. CT scan revealed acute subdural haematoma in 10, contusions in 4 patients, extradural haematoma and depressed fracture in 1 each, and diffuse axonal injury in 1 patient. Seven patients required surgery in the form of a decompressive hemicraniectomy. The histopathological analysis of the bilateral thalami showed evidence of congestion of the cerebral capillaries in 8 patients. Axonal retraction balls were seen in 8 patients, myelin breakdown products were seen in 14 patients and axonal swelling was seen in 14 patients. Conclusions: Thalamic injury is universal in the setting of severe TBI in patients who have decreased survival and may be a significant factor for the poor outcome in these patients.
Aminopeptidase A contributes to the N-terminal truncation of amyloid beta-peptide
JOURNAL OF NEUROCHEMISTRY
Authors: Sevalle, Jean; Amoyel, Audrey; Robert, Philippe; Fournie-Zaluski, Marie-Claude; Roques, Bernard; Checler, Frederic
Abstract
Several lines of data previously indicated that N-terminally truncated forms of amyloid-beta (A beta) peptides are likely the earliest and more abundant species immunohistochemically detectable in Alzheimer's disease-affected brains. It is noteworthy that the free N-terminal residue of full-length A beta (fl-A beta) is an aspartyl residue, suggesting that A beta could be susceptible to exopeptidasic attack by aminopeptidase A (APA)-like proteases. In this context, we have examined whether APA could target A beta peptides in both cell-free and cellular models. We first show that the general aminopeptidase inhibitor amastatin as well as two distinct aminopeptidase A inhibitors EC33 and pl302 both significantly increase the recovery of genuine fl-A beta peptides generated by cells over-expressing Swedish-mutated beta amyloid precursor protein (APP) while the aminopeptidase N blocker pl250 did not modify fl-A beta recovery. In agreement with this observation, we establish that over-expressed APA drastically reduces, in a calcium dependent manner, fl-A beta but not APP IntraCellular Domain in a cell-free model of A beta production. In agreement with the above data, we show that recombinant APA degrades fl-A beta in a pl302-sensitive manner. Interestingly, we also show that EC33 and pl302 lower staurosporine-stimulated activation of caspase-3 in wild-type fibroblasts but not in beta APP/beta-amyloid precursor protein-like protein 2 (APLP2) double knockout fibroblasts, suggesting that protecting endogenous fl-A beta physiological production triggers neuroprotective phenotype. By contrast, EC33 does not modify staurosporine-induced caspase-3 activation in wild-type and Swedish-mutated beta APP-HEK293 expressing cells that display exacerbated production of A beta. Overall, our data establish that APA contributes to the N-terminal truncation of A beta and suggest that this cleavage is likely abrogating a protective function associated with physiological but not supraphysiological levels of genuine fl-A beta peptides.