- Email: [email protected]
CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease
Poster Presentations: P1 P1-099
THE EFFECT OF REPETITIVE MILD TRAUMATIC BRAIN INJURY ON THE PATHOLOGIES OF ALZHEIMER’S DISEASE
Thor Stein1, Victor Alvarez2, Ann McKee1, 1Boston VA Medical Center, Boston, Massachusetts, United States; 2Boston University, Boston, Massachusetts, United States. Contact e-mail: [email protected] Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease induced by repeated mild traumatic brain injuries (TBIs). It is a tauopathy characterized by neurofibrillary tangles and tau-positive processes that preferentially involve the cortical sulci, medial temporal lobe, diencephalon, and brainstem. In CTE the tau pathology is predominantly subpial, perivascular, and within the sulcal depths. This tau pathology may be due to vascular damage, disruptions of the blood brain barrier, and axonal injury- alterations that also have been linked to Alzheimer disease (AD). In fact, trauma is a known risk factor for AD, and multiple mild TBIs may play a causative role in the development of AD as well as CTE. Thus, we hypothesize that the distribution of AD pathologies is altered by the mechanical injury that occurs in those subjects with both CTE and AD. Methods: Immunohistochemistry, quantitative ELISA, and confocal microscopy were performed using antibodies against beta-amyloid, tau, GFAP, IBA-1, synaptophysin, and MAP-2 on fixed or frozen post-mortem brain tissue from subjects with CTE and AD and compared to subjects with CTE or AD alone. Protein levels at the depths of sulci were compared to gyral crests in brain regions both affected and not affected by CTE. Results: In subjects with both CTE and AD, beta-amyloid is greater within the sulcal depths as compared to the gyral crests while in AD the levels are similar. The increased sulcal beta-amyloid is associated with marked tau pathology within neuronal processes. Furthermore, the expression of tau isoforms is altered, and there is greater neuroinflammation in the white matter and at the sulcal depths in CTE and CTE-AD compared to AD. Conclusions: The pathologies of AD are altered in individuals with CTE and a history of repetitive mild TBIs, suggesting that trauma may initiate or accelerate these processes.
P1-100
P187 CBP GENE TRANSFER INCREASES BDNF LEVELS AND AMELIORATES LEARNING AND MEMORY DEFICITS IN A MOUSE MODEL OF ALZHEIMER’S DISEASE
Antonella Caccamo1, Salvatore Oddo1, 1University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States. Contact e-mail: [email protected] Background: Cognitive dysfunction and memory loss are common features of Alzheimer disease (AD). Abnormalities in the expression profile of immediate early genes (IEGs) that play a critical role in memory formation, such as the cAMP-response element binding protein (CREB), have been reported in the brains of AD patients. Methods: Using a mouse model of Alzheimer’s disease, we use a lentiviral delivery system to modify the activity of immediate early genes involved in learning and memory. Results: Here we show that Ab accumulation, which plays a primary role in the cognitive deficits of AD, interferes with CREB activity. We further show that restoring CREB function via brain viral delivery of the CREB-binding protein (CBP) improves learning and memory deficits in an animal model of AD. Notably, such improvements occur without changes in Ab and tau pathology, and instead are linked to an increase in the levels of the brain derived neurotrophic factor (BDNF). The resulting data suggest that Ab-induced learning and memory deficits are mediated by alterations in CREB function, as finding that restoring CREB activity by directly modulating CBP levels in the brains of adult mice is sufficient to ameliorate learning and memory. Conclusions: Increasing CBP expression in adult brains may be a valid therapeutic approach not just for AD but for a variety of brain disorders characterized by alterations in IEGs, further supporting the concept that viral vector delivery may be a viable therapeutic approach in neurodegenerative diseases.
THE EFFECT OF REPETITIVE MILD TRAUMATIC BRAIN INJURY ON THE PATHOLOGIES OF ALZHEIMER’S DISEASE
Thor Stein1, Victor Alvarez2, Ann McKee1, 1Boston VA Medical Center, Boston, Massachusetts, United States; 2Boston University, Boston, Massachusetts, United States. Contact e-mail: [email protected] Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease induced by repeated mild traumatic brain injuries (TBIs). It is a tauopathy characterized by neurofibrillary tangles and tau-positive processes that preferentially involve the cortical sulci, medial temporal lobe, diencephalon, and brainstem. In CTE the tau pathology is predominantly subpial, perivascular, and within the sulcal depths. This tau pathology may be due to vascular damage, disruptions of the blood brain barrier, and axonal injury- alterations that also have been linked to Alzheimer disease (AD). In fact, trauma is a known risk factor for AD, and multiple mild TBIs may play a causative role in the development of AD as well as CTE. Thus, we hypothesize that the distribution of AD pathologies is altered by the mechanical injury that occurs in those subjects with both CTE and AD. Methods: Immunohistochemistry, quantitative ELISA, and confocal microscopy were performed using antibodies against beta-amyloid, tau, GFAP, IBA-1, synaptophysin, and MAP-2 on fixed or frozen post-mortem brain tissue from subjects with CTE and AD and compared to subjects with CTE or AD alone. Protein levels at the depths of sulci were compared to gyral crests in brain regions both affected and not affected by CTE. Results: In subjects with both CTE and AD, beta-amyloid is greater within the sulcal depths as compared to the gyral crests while in AD the levels are similar. The increased sulcal beta-amyloid is associated with marked tau pathology within neuronal processes. Furthermore, the expression of tau isoforms is altered, and there is greater neuroinflammation in the white matter and at the sulcal depths in CTE and CTE-AD compared to AD. Conclusions: The pathologies of AD are altered in individuals with CTE and a history of repetitive mild TBIs, suggesting that trauma may initiate or accelerate these processes.
P1-100
P187 CBP GENE TRANSFER INCREASES BDNF LEVELS AND AMELIORATES LEARNING AND MEMORY DEFICITS IN A MOUSE MODEL OF ALZHEIMER’S DISEASE
Antonella Caccamo1, Salvatore Oddo1, 1University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States. Contact e-mail: [email protected] Background: Cognitive dysfunction and memory loss are common features of Alzheimer disease (AD). Abnormalities in the expression profile of immediate early genes (IEGs) that play a critical role in memory formation, such as the cAMP-response element binding protein (CREB), have been reported in the brains of AD patients. Methods: Using a mouse model of Alzheimer’s disease, we use a lentiviral delivery system to modify the activity of immediate early genes involved in learning and memory. Results: Here we show that Ab accumulation, which plays a primary role in the cognitive deficits of AD, interferes with CREB activity. We further show that restoring CREB function via brain viral delivery of the CREB-binding protein (CBP) improves learning and memory deficits in an animal model of AD. Notably, such improvements occur without changes in Ab and tau pathology, and instead are linked to an increase in the levels of the brain derived neurotrophic factor (BDNF). The resulting data suggest that Ab-induced learning and memory deficits are mediated by alterations in CREB function, as finding that restoring CREB activity by directly modulating CBP levels in the brains of adult mice is sufficient to ameliorate learning and memory. Conclusions: Increasing CBP expression in adult brains may be a valid therapeutic approach not just for AD but for a variety of brain disorders characterized by alterations in IEGs, further supporting the concept that viral vector delivery may be a viable therapeutic approach in neurodegenerative diseases.