Lena Cai

The majority of Alzheimer's disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aβ under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aβ sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aβ sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAβ expression, rescues cognition and reduces the formation of PAS granules.

Diabetes mellitus (DM) is one of the most devastating diseases that currently affects the aging population. Recent evidence indicates that DM is a risk factor for many brain disorders, due to its direct effects on cognition. New findings have shown that the microtubule-associated protein tau is pathologically processed in DM; however, it remains unknown whether pathological tau modifications play a central role in the cognitive deficits associated with DM. To address this question, we used a gain-of-function and loss-of-function approach to modulate tau levels in type 1 diabetes (T1DM) and type 2 diabetes (T2DM) mouse models. Our study demonstrates that tau differentially contributes to cognitive and synaptic deficits induced by DM. On one hand, overexpressing wild-type human tau further exacerbates cognitive and synaptic impairments induced by T1DM, as human tau mice treated under T1DM conditions show robust deficits in learning and memory processes. On the other hand, neither a reduction nor increase in tau levels affects cognition in T2DM mice. Together, these results shine new light onto the different molecular mechanisms that underlie the cognitive and synaptic impairments associated with T1DM and T2DM.

The majority of Alzheimer's disease (AD) cases are sporadic, which means that the disease originates spontaneously without any known cause. To date, no lab has succeeded in developing a model for sporadic AD, which represents one of the consequential hurdles remaining in the field. Thus, it is critical to study and elucidate factors and conditions that trigger the diseases in the 98% of patients that lack the known mutations that cause familial AD (FAD). Here, we introduce a novel animal model of sporadic AD (hAß-KI), in which the mouse Aβ encoding DNA sequence was replaced with the human Aβ sequence (which is known to more readily aggregate than the mouse Aß). We used a combination of genetic, biochemical, histological and behavioral approaches to generate and characterize this innovative AD model. DNA sequence analysis demonstrated that hAb-KI express humanized Ab and that expression of amyloid precursor protein (APP) was similar between wild type and hAb-KI mice. hAb-KI present with diffuse Ab aggregates from 18 months of age and no Congophilic or ThioS aggregates were observed. Cognitive deficits begin at 10 months in hAb-KI. Moreover, seeding experiments in which 8-month-old hAb-KI were inoculated with brain extract from AD patients with high pathology demonstrated a significant increase of plaque load. A highly innovative aspect of this study is that we generated the first Knock-in mice that express human non-mutated Aβ in the fully natural context of the endogenous mouse App gene and without the addition of any FAD mutations or overexpression of APP or its metabolites. This mouse model should enable a more physiologically relevant understanding of the underlying mechanisms driving AD pathology, by more closely recapitulating the pathological cascade of events that occurs in the majority of human AD patients.

The majority of Alzheimer's disease (AD) cases are sporadic, which means that the disease originates spontaneously, without any known cause. Today, no lab has succeeded in developing a model for sporadic AD, which represents one of the consequential hurdles remaining in the field. Thus, it is critical to study and elucidate factors and conditions that trigger the diseases in 98% of the patients. Here, I introduce the first animal model of sporadic AD, to which the consequential step involves the deletion of the mouse Aβ sequence and replacing it with the human Aβ sequence. We used a combination biochemical, histological and behavioral approaches to characterize this innovative AD model. DNA sequence analysis demonstrated that APPKI-hAβwt express humanized Ab and amyloid precursor protein (APP) were similar between non-transgenic and APPKI-hAβwt mice. APPKI-hAβwt express diffuse Aβ aggregates from 10 month of age and no Congofilic or ThioS aggregates were observed. In addition, cognitive deficits begin at 10 months in APPKI-hAβwt. A highly innovative aspect of this proposal is that we generated the first Knock-in mice that express human non-mutated Aβ in the fully natural context of the endogenous mouse APP gene and it does so without the addition of any FAD mutations, or overexpression of APP or its metabolites. This highly innovative mouse model pledge a much more physiologically relevant understanding of the underlying mechanisms driving AD pathology, by more closely recapitulating the pathological cascade of events that occurs in the majority of human AD patients.

Over the past two-decade researchers have focused their efforts on developing animal models to dissect the molecular mechanisms underlying AD, and to assist with the identification and development of potential therapies. Although these models have provided useful insights into the mechanisms of disease, the initial optimism for hastening drug development was perhaps premature, as successes in treating AD in mouse models have not been translated into the clinic. The discordance between preclinical efficacy in animal models and the lack of success during transition into clinical testing could be due to the significant overexpression of familial AD (FAD)-associated mutated proteins and the dependence of artificial transcriptional regulatory elements, among several other limitations. Therefore, new models are urgently needed to better understand pathophysiological events that occur in the sporadic form of the disease. We used a combination of genetic, biochemical, histological and behavioral approaches to generate and characterize a wildtype human Aβ knock-in mice. Our model, termed hAβ-KI, expresses wild-type human Aβ under the control of the endogenous mouse APP gene. The hAβ-KI mouse line develops age dependent increase in sparse Ab aggregates, cognitive and electrophysiological deficits. This knock-in model represents an important first step towards the development of next-generation animal models that hopefully will provide better predictive outcomes for human patients, which can turn into safe and effective clinical applications.