Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model

Abstract

Tau cleavage plays a crucial role in the onset and progression of Alzheimer’s Disease (AD), a widespread neurodegenerative disease whose incidence is expected to increase in the next years. While genetic and familial forms of AD (fAD) occurring early in life represent less than 1%, the sporadic and late-onset ones (sAD) are the most common, with ageing being an important risk factor. Intracerebroventricular (ICV) infusion of streptozotocin (STZ)—a compound used in the systemic induction of diabetes due to its ability to damage the pancreatic β cells and to induce insulin resistance—mimics in rodents several behavioral, molecular and histopathological hallmarks of sAD, including memory/learning disturbance, amyloid-β (Aβ) accumulation, tau hyperphosphorylation, oxidative stress and brain glucose hypometabolism. We have demonstrated that pathological truncation of tau at its N-terminal domain occurs into hippocampi from two well-established transgenic lines of fAD animal models, such as Tg2576 and 3xTg mice, and that it’s in vivo neutralization via intravenous (i.v.) administration of the cleavage-specific anti-tau 12A12 monoclonal antibody (mAb) is strongly neuroprotective. Here, we report the therapeutic efficacy of 12A12mAb in STZ-infused mice after 14 days (short-term immunization, STIR) and 21 days (long-term immunization regimen, LTIR) of i.v. delivery. A virtually complete recovery was detected after three weeks of 12A12mAb immunization in both novel object recognition test (NORT) and object place recognition task (OPRT). Consistently, three weeks of this immunization regimen relieved in hippocampi from ICV-STZ mice the AD-like up-regulation of amyloid precursor protein (APP), the tau hyperphosphorylation and neuroinflammation, likely due to modulation of the PI3K/AKT/GSK3-β axis and the AMP-activated protein kinase (AMPK) activities. Cerebral oxidative stress, mitochondrial impairment, synaptic and histological alterations occurring in STZ-infused mice were also strongly attenuated by 12A12mAb delivery. These results further strengthen the causal role of N-terminal tau cleavage in AD pathogenesis and indicate that its specific neutralization by non-invasive administration of 12A12mAb can be a therapeutic option for both fAD and sAD patients, as well as for those showing type 2 diabetes as a comorbidity.

Morphological and biomolecular targets in retina and vitreous from Reelin-deficient mice (Reeler): Potential implications for age-related macular degeneration in Alzheimer’s dementia

“…Of interest, the immunoreactivity for these AD markers increased in a time-dependent fashion, starting from p21, implying the development in adulthood. The presence of APP/Aβ1-42 deposits and overexpressed tau in the peripheral retina was previously reported in transgenic AD mice ( Ning et al, 2008 ; Dutescu et al, 2009 ; Kocherhans et al, 2010 ; Latina et al, 2021a ), and particularly this pathological expression was confirmed in post-mortem AD retinas ( den Haan et al, 2018 ). Gliosis, Drusen and APP/Aβ deposition represent common markers of neurodegeneration in AMD and AD retinas, resulting from damaged RGCs, activated Macroglia (Muller Cells and astrocytes) and reactive Microglia ( Lee and Landreth, 2010 ).…”

“…Paraffine-embedded retinas (9 Reeler and 9 WT; 1 retina = 5 slides = 3 optic fields per slide) were sectioned and subjected to double-immunofluorescence. Briefly, dewaxed and post-fixed (2% buffered ρ-Formaldehyde; PFA) sections were equilibrated in PBS [10 mM phosphate buffer and 137 mM NaCl; pH 7.5], quenched (10 mM NH 4 Cl), permeabilized (0.5% Triton X100 in PBS; PBS-TX) and probed with the following antibodies: anti-mouse APP (B4) (sc-28365; 1/100; Santa Cruz Biotechnology; Dallas, Texas, USA); anti-rabbit Aβ1-42 peptide (D54D2) (mAb #8243; 1:100; Cell Signalling Technology, Inc.; Danvers, Massachusetts, USA); anti-rabbit caspase-cleaved protein (CCP)-NH 2 tau 4268; 1/200 Amadoro et al, 2012 ; Latina et al, 2021a , b ) and anti-rabbit TLR4 (H-80) antibody (sc-10741; 1/100; Santa Cruz) as shown in Table 1A . The specific binding was detected using Cy2/Cy3-conjugated specie-specific secondary antibodies (1/500-1/700; Jackson ImmunoResearch Labs., Europe Ltd., Suffolk, UK).…”

“…Loss in synapses, amyloid β (Aβ) peptide aggregation and accumulation of tau neurofibrillary tangles into specific Central Nervous System (CNS) regions are mainly required for AD diagnosis ( Galasko and Shaw, 2017 ; Jack et al, 2017 ). An early accumulation of APP/Aβ and tau hyperphosphorylation, two hallmarks of brain neurodegeneration, also occur in retinas of experimental AD models and patients suffering from AD ( Oddo et al, 2003 ; Javaid et al, 2016 ; Czakó et al, 2020 ; Mei et al, 2020 ; Schultz et al, 2020 ; Gupta et al, 2021 ; Latina et al, 2021a ). Additionally, AD patients state visual deficits and retinal ultrastructural modifications, such as ganglion cell degeneration, nerve fiber layer (NFL) thinning and optic nerve degeneration ( Koronyo-Hamaoui et al, 2011 ; Schultz et al, 2020 ), supporting the notion that the retina embodies a valuable site for preclinical level of AD biomarkers research ( Cordeiro et al, 2010 ).…”

Shen Qi Wan Ameliorates Learning and Memory Impairment Induced by STZ in AD Rats through PI3K/AKT Pathway

“…In contrast, the pathophysiology of the ICV-STZ animal model is similar to that of AD patients [ 47 ]. Furthermore, ICV-STZ has now been found to induce cognitive impairment and neuron damage [ 48 ], oxidative stress [ 49 ] and glucose/energy metabolism damage in the brain [ 50 ], insulin resistance in the brain [ 51 , 52 ], and finally lead to Tau hyperphosphorylation and Aβ deposition [ 53 , 54 ].…”

Therapeutic Potential of Targeting Mitochondria for Alzheimer’s Disease Treatment

“…Furthermore, based on in vitro and in vivo evidence supporting the crucial role of Tau modifications in driving AD progression [40], administration of another mAb, called 12A12, turn out to be greatly effective in different preclinical AD animal models leading to 'significant improvements' of the main alterations associated with the disease. 12A12 has a very high specificity for a toxic AD-relevant Tau fragment that is capable of causing alterations mainly at the mitochondrial level [41]. This antibody has been developed by the research group coordinated by Pietro Calissano, longtime collaborator of the Nobel laureate Rita Levi-Montalcini, at the Ebri Foundation.…”